kaubiomed_gene_evidence.jsonl

{"gene": "MC4R", "focus": "obesity_membrane_gpcr", "uniprot": {"gene": "MC4R", "status": "ok", "accession": "P32245", "entry": "MC4R_HUMAN", "protein_name": "Melanocortin receptor 4", "function": "G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha- and beta-MSH) and corticotropin/ACTH, which are peptide products of the POMC precursor (PubMed:12646665, PubMed:14764818, PubMed:25163632, PubMed:32327598, PubMed:33858992, PubMed:8392067). Functions as a central component of the leptin-melanocortin pathway, which is essential for maintaining energy homeostasis (PubMed:32327598, PubMed:33858992). Upon activation, couples to G(s) protein, stimulating adenylate cyclase and the cAMP-dependent signaling pathway, which promotes anorexogenic signaling in the hypothalamus and contributes to a negative energy balance (PubMed:12588803, PubMed:14764818, PubMed:25163632, PubMed:33858992). Regulates food intake: activation by agonists suppresses appetite, whereas the antagonist Agouti-related protein/AGRP precludes agonist-induced signaling, thereby stimulating appetite (PubMed:9311920, PubMed:29311635). Modulates the firing activity of neurons in paraventricular nucleus (PVN) of the hypothalamus via alpha-MSH and AGRP regulation of inwardly rectifying potassium channel KCNJ13 closure, independently of G(s) signaling (PubMed:32327598). In the PVN, also interacts with opsin 3/OPN3, which couples to G(i/o) proteins to inhibit MC4R-mediated cAMP signaling, thereby promoting food intake (PubMed:39951488). In intestinal epithelial cells, contributes to inhibition of hepatic glucose production via nesfatin-1/NUCB2, leading to increased cAMP levels and glucagon-like peptide 1 (GLP-1) secretion (PubMed:39562740). Interaction with MGRN1 displaces the G(s) protein, further decreasing MC4R signaling activity (PubMed:19737927). Also activated by gamma-MSH, though with low potency (PubMed:8392067)", "disease": ""}, "pubmed": {"gene": "MC4R", "status": "ok", "articles": [{"pmid": "42167238", "title": "A phenome-wide association study of CNVs genotyped from genome sequencing read depth in the UK Biobank.", "journal": "American journal of human genetics", "year": "2026", "abstract": "We developed a read-depth-based approach that allows accurate and scalable copy-number genotyping from genome sequencing data, including mosaic, recurrent, and multiallelic copy-number variants (CNVs) that are difficult to genotype using other methods. We genotyped each 5-kb segment throughout the genome in the UK Biobank cohort and performed phenome-wide association studies (PheWASs) using 13,215 traits under three different association models, identifying 501 CNVs associated with 1,537 traits. Of these, almost 75% were not found by comparable single-nucleotide variant (SNV)-based PheWASs. We detected signals with multiallelic CNVs, including a coding repeat within MUC1 (mucin 1, cell-surface associated) associated with stomach/duodenal polyps (p = 7.7 \u00d7 10-24), copy number of AMY1 (amylase alpha) genes associated with denture use (p = 2.4 \u00d7 10-29), and a multiallelic coding CNV within NEB, encoding muscle sarcomere protein, associated with muscle mass (p = 9.7 \u00d7 10-24). We also identified intergenic CNVs with effects on traits known to be regulated by nearby genes. For example, carriers of rare non-coding deletions \u223c100 kb upstream of MC4R, coding mutations in which are the most common cause of monogenic obesity, were, on average, \u223c14 kg heavier than control subjects. In some cases, non-coding CNVs encompassed regulatory elements of the adjacent candidate gene. Using burden tests, we identified an excess of rare damaging non-coding SNVs within some of these regulatory elements associated with the same traits observed in CNV carriers. Our study provides a detailed map of functional CNVs, including complex loci that are recalcitrant to other methods, providing numerous insights into their effects on human traits."}, {"pmid": "42061509", "title": "Genetic variability in the leptin-melanocortin pathway and its role in weight loss.", "journal": "Molecular metabolism", "year": "2026", "abstract": "Obesity is a multifactorial disease characterized by an excessive and abnormal accumulation of body fat that results from both genetic and environmental factors. In this review, we revisited the literature on the variability of obesity-associated genes and their impact on the effectiveness of obesity treatment interventions. Individuals harboring variants of these genes were found to have either better or worse outcomes after weight loss therapies. The majority of the genetic variants were identified in genes that play a role in the leptin-melanocortin pathway (LEPR, NPY, POMC, MC4R, GHRL, GHSR, GLP-1R, BDNF), which regulates food intake and energy expenditure. Both these processes are key elements for energy homeostasis, therefore relevant for the success/failure of weight loss strategies. Some genetic alterations were found to modulate the outcomes of different weight loss interventions, while others were only linked to the effectiveness of bariatric surgery, according to the studies here included and available. Herein, we revisited the most relevant molecular data, with a primarily focus on human studies, concerning how the genetic background influences the outcomes of weight loss interventions. Our aim is to gather relevant information on the genetic data related to weight loss strategies that can be compelling to guide clinical decisions, setting realistic expectations, and ultimately improving the long-term health conditions of individuals with obesity."}, {"pmid": "41992546", "title": "Melanocortin 3 Receptors Do Not Specifically Localize to Primary Cilia in Cultured Human and Rodent Neurons.", "journal": "Cell biochemistry and function", "year": "2026", "abstract": "The melanocortin-3 receptor (MC3R) and the melanocortin-4 receptor (MC4R), both expressed in hypothalamic nuclei, are key downstream effectors of leptin signaling and play important roles in energy homeostasis. While pathogenic variants in the MC4R gene represent the most common cause of monogenic obesity, the clinical significance of MC3R variants is less clear. MC4R localizes to the primary cilium, a sensory organelle present on nearly all human cells. To better understand the pathophysiological mechanisms of MC3R variants, we investigated whether MC3R localizes to the primary cilium and assessed the impact of rare MC3R variants identified in individuals with obesity on ciliary expression. Using human RPE cells, human NGN2-induced iNeurons, and primary mouse hypothalamic neurons, we found that, in contrast to MC4R, neither wild type MC3R nor rare MC3R variants localized specifically to the primary cilium in vitro in any cell type, including hypothalamic neurons. These findings suggest that MC3R and MC4R may utilize distinct signaling pathways or that additional factors, such as accessory proteins, are required for MC3R targeting to primary cilia in vivo. Further studies are needed to clarify the role of MC3R variants in monogenic obesity and their broader implications for human disease."}, {"pmid": "41935248", "title": "Cellular signatures of melanocortin pathway genes across the locus coeruleus.", "journal": "Acta neuropathologica communications", "year": "2026", "abstract": "Obesity and Alzheimer\u2019s disease (AD) are epidemiologically associated. The locus coeruleus (LC)\u2014the brain\u2019s primary and most significant source of norepinephrine\u2014is one of the earliest sites of neurodegeneration in AD. The LC participates in feeding behavior through connections with the hypothalamus. The cellular composition of the LC has been characterized at single-cell resolution. However, the constituent cellular signatures of genes related to energy homeostasis\u2014such as the melanocortin pathway genes\u2014in the LC are unclear. We performed single-nucleus RNA sequencing and spatial transcriptomics (Visium) in the human LC, and HiPlex RNAscope in the LC of mice. The melanocortin pathway gene MRAP2 was expressed in the majority of DBH neurons across the LC. Mrap2 was also co-expressed with AD-associated genes such as App, Psen1, Psen2, and Sorl1. More than 20% of Dbh neurons in the LC were positive for Mrap2, App, Psen1, and Psen2. Mrap2 is expressed in the central nervous system and modulates the trafficking and signaling of all five G-protein coupled receptors (GPCRs) of the melanocortin receptor family: Mc1r, Mc2r, Mc3r, Mc4r, and Mc5r. In mice, among the melanocortin receptors, Mc5r showed the highest co-expression with Mrap2, accounting for 17.9% of Mrap2-positive cells, followed by Mc2r with 10.9% of Mrap2-positive cells. Mc1r, Mc3r, and Mc4r showed very limited co-expression with Mrap2. Our study reveals that many Mrap2-positive cells do not express any melanocortin receptor genes, warranting future studies into metabolically relevant GPCRs downstream of MRAP2 in the LC. In summary, our study characterizes melanocortin molecular substrates in the human and mouse LC and highlights MRAP2 as a potential link between pathways of energy homeostasis and neurodegeneration. The online version contains supplementary material available at 10.1186/s40478-026-02287-x."}, {"pmid": "41933839", "title": "Maternal Nutrition and Hypothalamic Programming of Offspring Metabolic Health.", "journal": "The Journal of nutrition", "year": "2026", "abstract": "The hypothalamus plays a central role in regulating metabolism by integrating hormonal and nutrient-derived signals to maintain energy homeostasis across the life span. Maternal nutritional status during critical windows of development is a major environmental factor that can permanently alter this regulation. Both maternal overnutrition and undernutrition have been shown to disturb circulating leptin, insulin, and glucagon-like peptide-1 (GLP-1), and to disrupt the normal development of hypothalamic nuclei implicated in energy balance. Experimental and clinical studies indicate that these insults miswire proopiomelanocortin (POMC) and neuropeptide Y/agouti-related peptide (NPY/AgRP) pathways, alter leptin and insulin receptor signaling, trigger neuroinflammation, glial and vascular changes, and are accompanied by enduring epigenetic alterations, including DNA methylation and chromatin remodeling at genes such as Pomc, Npy, Mc4r, Lepr, and Insr. Together, these adaptations establish new set points for appetite, energy expenditure, and glucose regulation, thereby increasing the lifelong risk of obesity and type 2 diabetes in the offspring. In this narrative review, we synthesize evidence from animal models and human studies linking maternal nutrition to hypothalamic programming via leptin, insulin, and GLP-1. We also highlight major gaps, including limited data on GLP-1 in maternal undernutrition, the specific role of individual micronutrients, and the timing and reversibility of hypothalamic programming, to inform future mechanistic, translational, and preventive research."}]}, "alphafold": {"status": "ok", "uniprot": "P32245", "entry_id": "AF-P32245-F1", "uniprot_start": 1, "uniprot_end": 332, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P32245-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P32245-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P32245-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 307677, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P32245-F1.cif", "pdb_bytes": 215540, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P32245-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "MC4R"}}
{"gene": "LEP", "focus": "obesity_endocrine", "uniprot": {"gene": "LEP", "status": "ok", "accession": "P41159", "entry": "LEP_HUMAN", "protein_name": "Leptin", "function": "Key player in the regulation of energy balance and body weight control. Once released into the circulation, has central and peripheral effects by binding LEPR, found in many tissues, which results in the activation of several major signaling pathways (PubMed:15899045, PubMed:17344214, PubMed:19688109). In the hypothalamus, acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones. In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic for endothelial cell and affects innate and adaptive immunity (By similarity) (PubMed:11460888, PubMed:19688109, PubMed:24340098, PubMed:25060689, PubMed:8589726). In the arcuate nucleus of the hypothalamus, activates by depolarization POMC neurons inducing FOS and SOCS3 expression to release anorexigenic peptides and inhibits by hyperpolarization NPY neurons inducing SOCS3 with a consequent reduction on release of orexigenic peptides (By similarity). In addition to its known satiety inducing effect, has a modulatory role in nutrient absorption. In the intestine, reduces glucose absorption by enterocytes by activating PKC and leading to a sequential activation of p38, PI3K and ERK signaling pathways which exerts an inhibitory effect on glucose absorption (PubMed:24340098). Acts as a growth factor on certain tissues, through the activation of different signaling pathways increases expression of genes involved in cell cycle regulation such as CCND1, via JAK2-STAT3 pathway, or VEGFA, via MAPK1/3 and PI3K-AKT1 pathways (By similarity) (PubMed:17344214). May also play an apoptotic role via JAK2-STAT3 pathway and up-regulation of BIRC5 expression (PubMed:18242580). Pro-angiogenic, has mitogenic activity on vascular endothelial cells and plays a role in matrix remodeling by regulating the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) (PubMed:11460888). In innate immunity, modulates the activity and function of neutrophils by increasing chemotaxis and the secretion of oxygen radicals. Increases phagocytosis by macrophages and enhances secretion of pro-inflammatory mediators. Increases cytotoxic ability of NK cells (PubMed:12504075). Plays a pro-inflammatory role, in synergy with IL1B, by inducing NOS2 which promotes the production of IL6, IL8 and Prostaglandin E2, through a signaling pathway that involves JAK2, PI3K, MAP2K1/MEK1 and MAPK14/p38 (PubMed:15899045, PubMed:19688109). In adaptive immunity, promotes the switch of memory T-cells towards T helper-1 cell immune responses (By similarity). Increases CD4(+)CD25(-) T-cell proliferation and reduces autophagy during TCR (T-cell receptor) stimulation, through MTOR signaling pathway activation and BCL2 up-regulation (PubMed:25060689)", "disease": ""}, "pubmed": {"gene": "LEP", "status": "ok", "articles": [{"pmid": "42233116", "title": "Evaluation of Synergic Effects of Molybdenum Disulfide Treatment and Near-Infrared Radiation on Human Mesenchymal Stem Cells.", "journal": "Journal of lasers in medical sciences", "year": "2026", "abstract": "Introduction: Molybdenum disulfide (MoS2), as an anticancer reagent, can absorb near-infrared (NIR) wavelengths in phototherapy. In the present study, the synergic effect of MoS2 (in nanostructure) and NIR radiation on human mesenchymal stem cells (hMSCs) was evaluated via protein-protein interaction (PPI) network analysis. Methods: Gene expression profiles of hMSCs were extracted from the Gene Expression Omnibus (GEO) database and analyzed via PPI network analysis. The validity of findings was assessed via the Kaplan-Meier Plotter. Results: FN1, ACTA2, CCL2, CXCL8, FBN1, and LEP genes were selected as hub genes among 121 recognized differentially expressed genes (DEGs) as the targeted genes by the synergic effects of MoS2 and NIR radiation. Kaplan-Meier Plotter analysis demonstrated that FN1 suppression by MoS2 and NIR radiation can significantly increase the overall survival of patients with gastric cancer, lung cancer, ovarian cancer, and myeloma. Conclusion: In conclusion, findings indicate that the anticancer property of MoS2 is intensified in the condition of NIR radiation. Therefore, MoS2 is a suitable photosensitizer reagent in photodynamic therapy."}, {"pmid": "42056985", "title": "Adherence to the EAT-Lancet Diet, plasma proteomics, and risk of venous thromboembolism: a large-scale prospective cohort study.", "journal": "BMC medicine", "year": "2026", "abstract": "The EAT Lancet diet is increasingly recognized for its simultaneous benefits to human and planetary health. Its key components are known to exert anti-inflammatory and antiplatelet effects; however, the potential association between adherence to the EAT\u2011Lancet diet and incident venous thromboembolism (VTE), as well as the underlying biological mechanisms, remains unclear. This prospective study involved 201,695 UK Biobank participants who were free of VTE at baseline, and integrated large-scale Olink plasma proteomics to identify diet-related molecular signatures. Adherence to the EAT-Lancet diet was quantified using two validated indices. Cox models were employed to evaluate associations between EAT-Lancet diet, plasma proteins, and incident VTE (including deep vein thrombosis [DVT] and pulmonary embolism [PE]). Mediation analyses quantified the role of plasma proteins. During a median follow-up of 13.77 years, participants in the highest adherence group of the Stubbendorff index showed lower risks of VTE (HR\u2009=\u20090.809, 95% CI: 0.750-0.874), DVT (HR\u2009=\u20090.856, 95% CI: 0.781-0.938), and PE (HR\u2009=\u20090.754, 95% CI: 0.678-0.838). Consistent protective associations were observed with the Knuppel index. Mediation analyses identified 94 shared plasma protein mediators, with mediation proportions ranging from -\u20094.77% to 8.45% of the association, among which FABP4, LEP, and ENPP6 were the top-ranked mediators. The overall proteomic signature mediated 59.19% (95% CI: 27.02%-92.15%) and 40.10% (95% CI: 14.53%-65.96%) of the associations between the Stubbendorff and Knuppel index and incident VTE, respectively. Higher adherence to the EAT-Lancet diet is significantly associated with a reduced risk of incident VTE, DVT, and PE, with plasma proteins potentially mediating this effect."}, {"pmid": "41924527", "title": "Insulin-stimulated glucose uptake is impaired in senescent human adipocytes.", "journal": "Frontiers in endocrinology", "year": "2026", "abstract": "Cell senescence, a state of cell cycle arrest induced by intrinsic or extrinsic stress, is linked to aging and aging-associated diseases. Senescence markers are elevated in adipose tissue with age and in obesity. Recently, it was shown that human mature adipocytes can undergo senescence in response to hyperinsulinemia. However, the functional consequences of adipocyte cell senescence remain poorly understood. To study the impact of cellular senescence on human adipocyte function, we induced senescence in differentiated primary human preadipocytes (referred to as human adipocytes) using nutlin-3a, doxorubicin and etoposide. Expression of senescence markers, insulin receptor signaling, response to lipolytic stimuli and insulin mediated glucose uptake were investigated. The senescence-inducing compounds increased expression of senescence markers p21, p53, activity of senescence-associated \u03b2-galactosidase (SA-\u03b2gal) and secretion of senescence-associated secreted factors (SASP). We showed that insulin-stimulated glucose uptake, but not basal glucose uptake, was significantly reduced in senescent adipocytes. Insulin receptor signaling was largely unaffected, while expression of insulin receptor signaling proteins and especially GLUT4 expression were reduced. Expression of some adipocyte marker genes, including ADIPOQ, LEP, PNPLA2, LIPE and PPAR\u03b32, and secretion of adiponectin were reduced in the senescent adipocytes. In contrast, lipolytic capacity of senescent adipocytes was largely unaffected. Our findings indicate that cellular senescence impairs insulin-stimulated glucose uptake but not lipolytic capacity; changes that may contribute to impaired glucose control and ectopic fat accumulation."}, {"pmid": "41675316", "title": "Leptin-dependent fat accumulation triggers autophagy in metabolic dysfunction-associated steatohepatitis model.", "journal": "Translational gastroenterology and hepatology", "year": "2026", "abstract": "Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic syndrome characterized by increased fat storage in hepatocytes. In the hepatocytes, autophagy protects against cytotoxic stress and harmful cellular conditions. In the hepatic stellate cells (HSCs), autophagy exerts pro-fibrotic properties and promotes the release of pro-inflammatory metabolites. We investigated the modulation of autophagy as a therapeutic approach for MASLD. Murine liver tissue and human hepatic cells were analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot. Real time fluorescence was performed to monitor the autophagy maturation process. Accumulation of fat was detected by Oil Red O staining. Collagen fibers were detected by picrosirius staining under polarized light. The loss of leptin in obese mice affected by metabolic dysfunction-associated steatohepatitis (MASH) promoted the over-expression of Becn1, Map1lc3b, Sqstm1, Uvrag and Prkaa1_2 and the accumulation of their proteins. The oleic acid caused an accumulation of fat, followed by the reduction of the autophagy proteins and the increase of the P-AMPK-\u03b1 in LEP-/- HepG2 cells and the maturation of autophagosome vesicles in LEP-/- Hep3B cells. Oleic acid increased the accumulation of fat in human HSCs and the COL1A1 transcript level, but not the collagen I fibers. BECN1 and MAP1LC3B were up-regulated. Instead, all the autophagy proteins were downregulated, but not P-AMPK-\u03b1. Instead, the treatment with caffeine prompted neither the transactivation nor the autophagy. Leptin loss contributes to the autophagy process in obese mice. The administration of oleic acid in LEP-/- cells prompted autophagy not only in hepatocyte-like cells but also in human HSCs."}, {"pmid": "41515960", "title": "The Influence of Cisplatin on Functionality and Surface Characteristics of Mesenchymal Stromal Cells In Vitro.", "journal": "International journal of molecular sciences", "year": "2025", "abstract": "Mesenchymal stromal cells (MSCs) are multipotent and play an important role in regenerative processes such as wound healing. Data on possible changes and functional restrictions of MSCs due to cisplatin chemotherapy, for example, in the treatment of head and neck cancer, diverge. The aim of this study was to evaluate the influence of cisplatin on MSCs with regard to their defining characteristics and their ability to differentiate and to migrate. MSCs from four human donors (a 59-year-old man, a 63-year-old woman, a 70-year-old man, and a 61-year-old man) were cultured in vitro with and without cisplatin for 24 h, and toxic and subcytotoxic concentrations were determined using an MTT. We then examined the surface phenotype markers (flow cytometry), migration (scratch assay), histological differentiation markers (adipo-, chondro-, osteogenic), and the expression of selected line-associated genes in real-time quantitative PCR (RT-qPCR) (LEP, SOX9, RUNX2). These characteristics were evaluated after treatment with different subcytotoxic, clinically relevant doses of cisplatin. Flow cytometry confirmed the presence of MSCs-characteristic surface markers, which remained stable under treatment with subcytotoxic doses of cisplatin. Cisplatin exposure reduced the mRNA abundance of leptin (a marker for adipogenic differentiation) but increased SOX9 mRNA abundance (chondrogenic differentiation). RUNX (osteogenic differentiation) did not change post cisplatin exposure. Histological analysis showed no difference with regard to osteogenic, chondrogenic, and adipogenic differentiation at doses up to 10 \u03bcM cisplatin. Cell migration was not restricted by cisplatin exposure under the conditions used here. The characteristics of MSCs were not different to controls post cisplatin exposure. mRNA analysis suggested induced changes by cisplatin, although this effect was not histologically detectable even at high doses. Based on the single-molecule markers used here, indications for an inhibitory effect of cisplatin on adipogenic differentiation and a rather enhancing effect on chondrogenic and osteogenic differentiation may be hypothesized. The process observed here could further aggravate the already serious problem of malnutrition in head and neck cancer patients, for example. Taken together though, our study confirms overall MSCs tolerance towards cisplatin."}]}, "alphafold": {"status": "ok", "uniprot": "P41159", "entry_id": "AF-P41159-F1", "uniprot_start": 1, "uniprot_end": 167, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P41159-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P41159-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P41159-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 163349, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P41159-F1.cif", "pdb_bytes": 111131, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P41159-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "LEP"}}
{"gene": "LEPR", "focus": "obesity_receptor", "uniprot": {"gene": "LEPR", "status": "ok", "accession": "P48357", "entry": "LEPR_HUMAN", "protein_name": "Leptin receptor", "function": "Receptor for hormone LEP/leptin (Probable) (PubMed:22405007). On ligand binding, mediates LEP central and peripheral effects through the activation of different signaling pathways such as JAK2/STAT3 and MAPK cascade/FOS. In the hypothalamus, LEP acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones (By similarity) (PubMed:9537324). In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic and affects innate and adaptive immunity (PubMed:12504075, PubMed:25060689, PubMed:8805376). Control of energy homeostasis and melanocortin production (stimulation of POMC and full repression of AgRP transcription) is mediated by STAT3 signaling, whereas distinct signals regulate NPY and the control of fertility, growth and glucose homeostasis. Involved in the regulation of counter-regulatory response to hypoglycemia by inhibiting neurons of the parabrachial nucleus. Has a specific effect on T lymphocyte responses, differentially regulating the proliferation of naive and memory T -ells. Leptin increases Th1 and suppresses Th2 cytokine production (By similarity) May transport LEP across the blood-brain barrier. Binds LEP and mediates LEP endocytosis. Does not induce phosphorylation of and activate STAT3 Antagonizes Isoform A and isoform B-mediated LEP binding and endocytosis", "disease": ""}, "pubmed": {"gene": "LEPR", "status": "ok", "articles": [{"pmid": "42061509", "title": "Genetic variability in the leptin-melanocortin pathway and its role in weight loss.", "journal": "Molecular metabolism", "year": "2026", "abstract": "Obesity is a multifactorial disease characterized by an excessive and abnormal accumulation of body fat that results from both genetic and environmental factors. In this review, we revisited the literature on the variability of obesity-associated genes and their impact on the effectiveness of obesity treatment interventions. Individuals harboring variants of these genes were found to have either better or worse outcomes after weight loss therapies. The majority of the genetic variants were identified in genes that play a role in the leptin-melanocortin pathway (LEPR, NPY, POMC, MC4R, GHRL, GHSR, GLP-1R, BDNF), which regulates food intake and energy expenditure. Both these processes are key elements for energy homeostasis, therefore relevant for the success/failure of weight loss strategies. Some genetic alterations were found to modulate the outcomes of different weight loss interventions, while others were only linked to the effectiveness of bariatric surgery, according to the studies here included and available. Herein, we revisited the most relevant molecular data, with a primarily focus on human studies, concerning how the genetic background influences the outcomes of weight loss interventions. Our aim is to gather relevant information on the genetic data related to weight loss strategies that can be compelling to guide clinical decisions, setting realistic expectations, and ultimately improving the long-term health conditions of individuals with obesity."}, {"pmid": "42003764", "title": "Systemic and Local Adiposity in the Bone Marrow Microenvironment Associated With Improved Prognosis in Hodgkin Lymphoma: Imaging and Molecular Analysis.", "journal": "International journal of cancer", "year": "2026", "abstract": "Excess adiposity has been associated with Hodgkin lymphoma (HL) development, but its implications remain unclear. Bone marrow (BM), a frequent extranodal involvement site, contains both red and fatty yellow marrow. We investigated whether obesity influences HL outcomes and characterized the BM and cytokine profiles. In this retrospective study, HL patients were analyzed to assess the association between obesity with relapse and mortality. Yellow and red marrow composition were evaluated using CT imaging and correlated with HL outcomes. A nested study analyzed cytokines in the interstitial marrow fluid (IMF) and in circulation of HL patients, in comparison to a control group of healthy blood donors. Further, in\u00a0vitro functional analyses were performed. Overweight/obesity in HL patients was associated with lower rates of BM involvement, disease relapse, and mortality. Moreover, dense yellow marrow was related to increased risk of death. HL subjects had elevated levels of adiponectin in IMF compared to marrow donors, whereas higher insulin, interleukin 8, and osteoprotegerin levels in IMF were associated with shorter time to relapse. At the molecular level in BM, HL patients had overexpression of LEPR and IGFBP3 in adipocytes, while stromal cells overexpressed IGF-axis receptors. In\u00a0in vitro studies, human recombinant IGF-1 significantly induced the L428 HL cell line proliferation, which when combined with IGFBP-3 modified apoptosis. The current findings suggest that obesity is associated with a lower incidence of BM involvement and mortality in patients with HL. The obesity together with HL mechanistically influences systemic and local BM cytokine production, thereby impacting HL fate."}, {"pmid": "41988726", "title": "Leptin Receptor Fibroblasts Are Preferential Contributors to Cardiac Fibrosis.", "journal": "Circulation research", "year": "2026", "abstract": "Cardiac fibrosis, a hallmark of heart failure and an unmet clinical need, arises from pathological activation of preexisting cardiac fibroblasts (CFs), but the contribution of CF heterogeneity to this process remains unclear. Murine models were used to lineage trace or deplete a specific sub-population of CFs at baseline and after myocardial infarction. Transcriptional and epigenetic differences between fibroblast subsets were assessed using next-generation sequencing. Conservation in humans was evaluated through single-cell RNA-seq data sets and histological examination. In mice, fibroblasts were the sole cardiac cell type expressing the signaling-capable isoform of the LepR (leptin receptor). LepR+ CFs emerged neonatally, occupied a defined niche in the coronary adventitia, exhibited enhanced hedgehog signaling, and responded to leptin. After myocardial infarction, LepR-Cre+ CFs proliferated more than interstitial CFs, became a predominant fibroblast lineage in the scar, and their genetic ablation reduced fibrosis while improving function. LepR+ CFs were also detected in the human heart, where they were embedded in an adipocyte-rich niche. These findings identify adventitial fibroblasts as key drivers of pathological remodeling and demonstrate that fibroblasts, rather than cardiomyocytes, are the principal responders to leptin in the heart, redefining how this major endocrine pathway influences cardiac remodeling and disease."}, {"pmid": "41933839", "title": "Maternal Nutrition and Hypothalamic Programming of Offspring Metabolic Health.", "journal": "The Journal of nutrition", "year": "2026", "abstract": "The hypothalamus plays a central role in regulating metabolism by integrating hormonal and nutrient-derived signals to maintain energy homeostasis across the life span. Maternal nutritional status during critical windows of development is a major environmental factor that can permanently alter this regulation. Both maternal overnutrition and undernutrition have been shown to disturb circulating leptin, insulin, and glucagon-like peptide-1 (GLP-1), and to disrupt the normal development of hypothalamic nuclei implicated in energy balance. Experimental and clinical studies indicate that these insults miswire proopiomelanocortin (POMC) and neuropeptide Y/agouti-related peptide (NPY/AgRP) pathways, alter leptin and insulin receptor signaling, trigger neuroinflammation, glial and vascular changes, and are accompanied by enduring epigenetic alterations, including DNA methylation and chromatin remodeling at genes such as Pomc, Npy, Mc4r, Lepr, and Insr. Together, these adaptations establish new set points for appetite, energy expenditure, and glucose regulation, thereby increasing the lifelong risk of obesity and type 2 diabetes in the offspring. In this narrative review, we synthesize evidence from animal models and human studies linking maternal nutrition to hypothalamic programming via leptin, insulin, and GLP-1. We also highlight major gaps, including limited data on GLP-1 in maternal undernutrition, the specific role of individual micronutrients, and the timing and reversibility of hypothalamic programming, to inform future mechanistic, translational, and preventive research."}, {"pmid": "41919986", "title": "Unraveling the Molecular Pathways of Insulin-Producing Cells Derived From Placenta Multipotent Stem Cells via Multi-Omics Analysis.", "journal": "Proteomics", "year": "2026", "abstract": "Stem cell-derived insulin-producing cells (Ins-PCs) hold great promise for diabetes treatment. Placenta-derived multipotent stem cells (PMSCs) are considered an ideal source of Ins-PC generation due to their immunomodulatory and differentiation properties. However, the cellular and molecular pathways underlying PMSC differentiation to Ins-PCs have not been fully elucidated. In this study, PMSCs were isolated from human placenta and successfully differentiated into Ins-PCs using miRNA-181a mimics. Differentiated Ins-PCs produced a significant amount of insulin and upregulation of C-peptide, insulin, and MAFA expression, compared to undifferentiated control PMSCs. RNA sequencing and LC-MS/MS were performed to uncover the pathways involved in the Ins-PC differentiation process. RNA sequencing revealed the transcriptional landscape of PMSC-derived Ins-PC differentiation. Pathway analysis identified important pathways involved in the differentiation process, including Notch and Wnt/\u00df-catenin, and so forth. Proteomics analysis further affirmed the presence of key insulin pathway-related proteins involved in the differentiation of PMSCs into Ins-PCs, including LEPR, STC2, MAP2K2, and so forth. Moreover, integrated transcriptomic and proteomic analyses further highlighted LEPR as a potential key regulator for Ins-PC differentiation. These findings demonstrated the feasibility of generating Ins-PCs from PMSCs and identified potential signaling pathways and regulators underlying Ins-PC differentiation, supporting PMSCs as a promising stem cell source of cell-based therapy for diabetes treatment."}]}, "alphafold": {"status": "ok", "uniprot": "P48357", "entry_id": "AF-P48357-F1", "uniprot_start": 1, "uniprot_end": 1165, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P48357-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P48357-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P48357-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 1109159, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P48357-F1.cif", "pdb_bytes": 766016, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P48357-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "LEPR"}}
{"gene": "POMC", "focus": "obesity_neuropeptide", "uniprot": {"gene": "POMC", "status": "ok", "accession": "P01189", "entry": "COLI_HUMAN", "protein_name": "Pro-opiomelanocortin", "function": "Precursor protein of pituitary hormones that are involved in diverse physiological processes, including the regulation of energy balance, stress response, immune function and skin pigmentation Functions as a ligand for the melanocortin receptors MC1R, MC2R, MC3R and MC5R (PubMed:8396929, PubMed:8463333, PubMed:8636348). Activation of MC1R increases melanogenesis in melanocytes found in the skin and hair (PubMed:9620771). Binding to MC2R stimulates the adrenal glands to secrete cortisol (PubMed:8636348). Contributes to the regulation of energy homeostasis through activation of MC3R (Probable). Involved in the regulation exocrine gland function through MC5R activation (By similarity) Serves as a ligand for the melanocortin receptors MC1R, MC3R, MC4R and MC5R (PubMed:8392067, PubMed:8396929, PubMed:8463333). Activation of MC1R promotes melanogenesis in melanocytes of the skin and hair (PubMed:10403794, PubMed:9620771). Contributes to the regulation of energy homeostasis through activation of MC3R (Probable). Through MC4R activation, functions as an anorexigenic peptide (PubMed:8392067). Promotes immunosuppression and involved in the regulation exocrine gland function through MC5R activation (By similarity) Functions as a ligand for the melanocortin receptors MC1R, MC3R, MC4R and MC5R (PubMed:8396929, PubMed:8463333). Activation of MC1R increases melanogenesis in melanocytes found in the skin and hair (Probable). Contributes to the regulation of energy homeostasis through activation of MC3R (Probable). Through MC4R activation, functions as an anorexigenic peptide (PubMed:8392067). Involved in the regulation exocrine gland function through MC5R activation (By similarity) Functions as a ligand for the melanocortin receptors MC1R, MC3R, MC4R and MC5R (PubMed:8396929, PubMed:8463333). Activation of MC1R increases melanogenesis in melanocytes found in the skin and hair (Probable). Contributes to the regulation of energy homeostasis through activation of MC3R (Probable). Binds to MC4R with low potency (PubMed:8392067). Involved in the regulation exocrine gland function through MC5R activation (By similarity) Endogenous orexigenic opiate Endogenous opiate", "disease": ""}, "pubmed": {"gene": "POMC", "status": "ok", "articles": [{"pmid": "42276059", "title": "Scalable hypothalamic neuron differentiation from human pluripotent stem cells suitable for modeling metabolic disorders.", "journal": "Stem cell reports", "year": "2026", "abstract": "The hypothalamus, composed of multiple nuclei, is essential for maintaining the body's homeostasis. Within the mediobasal hypothalamus, the arcuate nucleus (ARC) contains key neuronal populations, including appetite-suppressing pro-opiomelanocortin (POMC) neurons that regulate energy and glucose balance. Here, we present a chemically defined, scalable method for differentiating human pluripotent stem cells (hPSCs) into hypothalamic neurons enriched for POMC cells, compatible with robotic cell culture platforms for high-throughput use. Neuronal identity was validated by MERFISH single-cell transcriptomics, RNA-Seq, ATAC-Seq, and comparison to human hypothalamus. The method is robust across multiple hPSC lines, showing consistent induction of ventral diencephalon and hypothalamic markers. Derived neurons display metabolic disease-relevant features, including body mass index (BMI)-associated gene enrichment, and ATAC-Seq identifies potential candidate regulatory regions linked to hypothalamic development and metabolic traits. Functional assays reveal neuronal responses to insulin and the GLP-1 receptor agonist Exendin-4, and transcriptional responses to altered glucose conditions. This platform delivers a physiologically relevant model of human hypothalamic neurons that enables deeper mechanistic and therapeutic studies of metabolic disease."}, {"pmid": "42061509", "title": "Genetic variability in the leptin-melanocortin pathway and its role in weight loss.", "journal": "Molecular metabolism", "year": "2026", "abstract": "Obesity is a multifactorial disease characterized by an excessive and abnormal accumulation of body fat that results from both genetic and environmental factors. In this review, we revisited the literature on the variability of obesity-associated genes and their impact on the effectiveness of obesity treatment interventions. Individuals harboring variants of these genes were found to have either better or worse outcomes after weight loss therapies. The majority of the genetic variants were identified in genes that play a role in the leptin-melanocortin pathway (LEPR, NPY, POMC, MC4R, GHRL, GHSR, GLP-1R, BDNF), which regulates food intake and energy expenditure. Both these processes are key elements for energy homeostasis, therefore relevant for the success/failure of weight loss strategies. Some genetic alterations were found to modulate the outcomes of different weight loss interventions, while others were only linked to the effectiveness of bariatric surgery, according to the studies here included and available. Herein, we revisited the most relevant molecular data, with a primarily focus on human studies, concerning how the genetic background influences the outcomes of weight loss interventions. Our aim is to gather relevant information on the genetic data related to weight loss strategies that can be compelling to guide clinical decisions, setting realistic expectations, and ultimately improving the long-term health conditions of individuals with obesity."}, {"pmid": "41933839", "title": "Maternal Nutrition and Hypothalamic Programming of Offspring Metabolic Health.", "journal": "The Journal of nutrition", "year": "2026", "abstract": "The hypothalamus plays a central role in regulating metabolism by integrating hormonal and nutrient-derived signals to maintain energy homeostasis across the life span. Maternal nutritional status during critical windows of development is a major environmental factor that can permanently alter this regulation. Both maternal overnutrition and undernutrition have been shown to disturb circulating leptin, insulin, and glucagon-like peptide-1 (GLP-1), and to disrupt the normal development of hypothalamic nuclei implicated in energy balance. Experimental and clinical studies indicate that these insults miswire proopiomelanocortin (POMC) and neuropeptide Y/agouti-related peptide (NPY/AgRP) pathways, alter leptin and insulin receptor signaling, trigger neuroinflammation, glial and vascular changes, and are accompanied by enduring epigenetic alterations, including DNA methylation and chromatin remodeling at genes such as Pomc, Npy, Mc4r, Lepr, and Insr. Together, these adaptations establish new set points for appetite, energy expenditure, and glucose regulation, thereby increasing the lifelong risk of obesity and type 2 diabetes in the offspring. In this narrative review, we synthesize evidence from animal models and human studies linking maternal nutrition to hypothalamic programming via leptin, insulin, and GLP-1. We also highlight major gaps, including limited data on GLP-1 in maternal undernutrition, the specific role of individual micronutrients, and the timing and reversibility of hypothalamic programming, to inform future mechanistic, translational, and preventive research."}, {"pmid": "41791764", "title": "Biomarkers of hypothalamic melanocortin activity in human energy balance.", "journal": "Journal of neuroendocrinology", "year": "2026", "abstract": "The hypothalamic melanocortin system, comprised of proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, regulates energy balance but studies in humans are limited by lack of biomarkers to assess brain melanocortin activity. Previous studies evaluated POMC concentrations in human CSF in relation to BMI and leptin and to weight loss, including pharmacotherapy with lorcaserin which targets POMC neurons, showing that lower baseline POMC predicted a better weight loss response to lorcaserin. We performed a retrospective analysis of baseline CSF POMC levels in 139 healthy weight-stable individuals without diabetes or neurologic disease who participated in previous studies, including a subgroup analysis of 70 subjects spread equally across the BMI spectrum (19.2-57.3) and in 97 subjects with obesity. POMC was measured in CSF and AgRP was measured in CSF and plasma by sensitive 2-site ELISAs. Mean CSF POMC was lower in individuals with elevated versus normal BMI (200 vs. 269 fmol/mL; p\u2009=\u2009.0003) and strong negative correlations between CSF POMC and both BMI and leptin were found in 70 subjects across the BMI spectrum (p\u2009<\u2009.0001); this remained significant in all 139 subjects but not in 97 with obesity. The cohort with obesity included some very low CSF POMC levels (bottom 10%) that do not overlap with non-obese subjects. Strong positive correlations were noted between CSF POMC and AgRP in both CSF and plasma in all groups, including the subgroup with obesity, providing evidence that activities of both sets of neurons may be linked independently of leptin and BMI. Importantly CSF POMC levels remained remarkably constant when nine weight-stable subjects were studied twice over several years. In summary, CSF POMC was lower in individuals with elevated BMI and correlated negatively with BMI and leptin across the BMI spectrum but not within a cohort with obesity. However, the cohort with obesity contained subjects with very low CSF POMC levels that may indicate POMC deficiency and predict treatment response to melanocortin agonists. It remains to be determined if alternative biomarkers associated with low CSF POMC can be identified for use in the clinical setting."}, {"pmid": "41579593", "title": "Generation and characterization of POMC-tdTomato reporter human pluripotent stem cell lines.", "journal": "Stem cell research", "year": "2026", "abstract": "Proopiomelanocortin (POMC) is a precursor polypeptide that undergoes extensive, tissue-specific post-translational processing. It is expressed in several tissues, including pituitary gland, hypothalamus, brain stem, and skin. The hypothalamic POMC neurons in the arcuate nucleus are major neuronal populations involved in the regulation of body weight. In these neurons, POMC is processed into several peptides, among them the anorexigenic alpha-melanocyte stimulating hormone. Thus, the POMC neurons in the ARC have been named \"satiety\" neurons and are highly desirable drug targets. Here, we performed CRISPR/Cas9-mediated insertion of tdTomato reporter at the endogenous POMC locus, enabling direct visualization of POMC expression through tdTomato fluorescence in human pluripotent stem cell (hPSC)-derived hypothalamic neurons. This reporter line enables real-time visualization of POMC neuron differentiation, and selective enrichment of these populations for molecular, functional, and pharmacological studies. This line is readily available as new alternative method (NAM) platform, to support disease modeling and drug discovery in metabolic and neuroendocrine disorders within a human context."}]}, "alphafold": {"status": "ok", "uniprot": "P01189", "entry_id": "AF-P01189-F1", "uniprot_start": 1, "uniprot_end": 267, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P01189-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P01189-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P01189-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 249006, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P01189-F1.cif", "pdb_bytes": 172691, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P01189-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "POMC"}}
{"gene": "SIM1", "focus": "obesity_neurodevelopment", "uniprot": {"gene": "SIM1", "status": "ok", "accession": "P81133", "entry": "SIM1_HUMAN", "protein_name": "Single-minded homolog 1", "function": "Transcriptional factor that may have pleiotropic effects during embryogenesis and in the adult", "disease": ""}, "pubmed": {"gene": "SIM1", "status": "ok", "articles": [{"pmid": "39019033", "title": "Rare variation in non-coding regions with evolutionary signatures contributes to autism spectrum disorder risk.", "journal": "Cell genomics", "year": "2024", "abstract": "Little is known about the role of non-coding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of non-coding regions: human accelerated regions (HARs), which show signatures of positive selection in humans; experimentally validated neural VISTA enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole-genome analysis of >16,600 samples and >4,900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly contribute, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in VEs near OTX1 and SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved non-coding regions in ASD risk and suggest potential mechanisms of how regulatory changes can modulate social behavior."}, {"pmid": "37790480", "title": "Rare variation in noncoding regions with evolutionary signatures contributes to autism spectrum disorder risk.", "journal": "medRxiv : the preprint server for health sciences", "year": "2023", "abstract": "Little is known about the role of noncoding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of noncoding regions: Human Accelerated Regions (HARs), which show signatures of positive selection in humans; experimentally validated neural Vista Enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole genome analysis of >16,600 samples and >4900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in a VE near SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved noncoding regions in ASD risk and suggest potential mechanisms of how changes in regulatory regions can modulate social behavior."}, {"pmid": "37703582", "title": "SUMO-3 promotes the ubiquitin-dependent turnover of TRIM55.", "journal": "Biochemistry and cell biology = Biochimie et biologie cellulaire", "year": "2024", "abstract": "Human muscle-specific RING fingers (MURFs) are members of the tripartite motif (TRIM) family of proteins characterized by their C-terminal subgroup one signature domain. MURFs play a role in sarcomere formation and microtubule dynamics. It was previously established that some TRIMs undergo post-translational modification by small ubiquitin-like modifier (SUMO). In this study, we explored the putative SUMOylation of MURF proteins as well as their interactions with SUMO. MURF proteins (TRIM54, TRIM55, and TRIM63) were not found to be SUMOylated. However, TRIM55 turnover by proteasomal and lysosomal degradation was higher upon overexpression of SUMO-3 but not of SUMO-1. Furthermore, it is predicted that TRIM55 contains two potential SUMO-interacting motifs (SIMs). We found that SIM1- and SIM2-mutated TRIM55 were more stable than the wild-type (WT) protein partly due to decreased degradation. Consistently, SIM-mutated TRIM55 was less polyubiquitinated than the WT protein, despite similar monoubiquitination levels. Using IF microscopy, we observed that SIM motifs influenced TRIM55 subcellular localization. In conclusion, our results suggest that SUMO-3 or SUMO-3-modified proteins modulate the localization, stability, and RING ubiquitin ligase activity of TRIM55."}, {"pmid": "35061034", "title": "Rare Variant Analysis of Obesity-Associated Genes in Young Adults With Severe Obesity From a Consanguineous Population of Pakistan.", "journal": "Diabetes", "year": "2022", "abstract": "Recent advances in genetic analysis have significantly helped in progressively attenuating the heritability gap of obesity and have brought into focus monogenic variants that disrupt the melanocortin signaling. In a previous study, next-generation sequencing revealed a monogenic etiology in \u223c50% of the children with severe obesity from a consanguineous population in Pakistan. Here we assess rare variants in obesity-causing genes in young adults with severe obesity from the same region. Genomic DNA from 126 randomly selected young adult obese subjects (BMI 37.2 \u00b1 0.3 kg/m2; age 18.4 \u00b1 0.3 years) was screened by conventional or augmented whole-exome analysis for point mutations and copy number variants (CNVs). Leptin, insulin, and cortisol levels were measured by ELISA. We identified 13 subjects carrying 13 different pathogenic or likely pathogenic variants in LEPR, PCSK1, MC4R, NTRK2, POMC, SH2B1, and SIM1. We also identified for the first time in the human, two homozygous stop-gain mutations in ASNSD1 and IFI16 genes. Inactivation of these genes in mouse models has been shown to result in obesity. Additionally, we describe nine homozygous mutations (seven missense, one stop-gain, and one stop-loss) and four copy-loss CNVs in genes or genomic regions previously linked to obesity-associated traits by genome-wide association studies. Unexpectedly, in contrast to obese children, pathogenic mutations in LEP and LEPR were either absent or rare in this cohort of young adults. High morbidity and mortality risks and social disadvantage of children with LEP or LEPR deficiency may in part explain this difference between the two cohorts."}, {"pmid": "34675538", "title": "Clinical Significance of ", "journal": "OncoTargets and therapy", "year": "2021", "abstract": "Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney tumors, accounting for the majority of deaths from genitourinary cancers. The currently used nomograms for predicting patient outcomes are based on clinical-pathological characteristics only; however, a significant number of ccRCC survivors with similar radiological and histological features still demonstrate a different clinical course of the disease. This study aimed at the identification of novel DNA methylation biomarkers for the monitoring of patients with ccRCC. Gene expression profiling by SurePrint G3 Human GE 8\u00d760K Microarrays was performed in 4 ccRCC tissues and adjacent non-cancerous renal tissue (NRT) samples. Four down-regulated genes were selected for further DNA methylation status analysis in 123 ccRCC and 45 NRT samples using methylation-specific PCR (MSP). DNA methylation changes of ADAMTS19, BMP7, SIM1, and SFRP1 were cancer-specific with significantly (P<0.050) higher methylation frequency (37%, 20%, 18%, and 42%, respectively) in tumor tissues. The methylated status of at least one gene was significantly related to various clinical-pathological parameters, including tumor size, Fuhrman and WHO/ISUP grades, intravascular invasion, and necrosis. Moreover, the methylated status of multimarker panel ADAMTS19, BMP7 & SFRP1 was predictive for poorer overall survival (HR, 4.11; 95% CI, 1.22-13.86). In conclusion, DNA methylation of the three-gene panel consisting of ADAMTS19, BMP7 & SFRP1 supposedly predicts the outcome of patients diagnosed with ccRCC and possibly might be used to enrich the current prognostic tools."}]}, "alphafold": {"status": "ok", "uniprot": "P81133", "entry_id": "AF-P81133-F1", "uniprot_start": 1, "uniprot_end": 766, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P81133-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P81133-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P81133-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 697322, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P81133-F1.cif", "pdb_bytes": 496286, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P81133-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "SIM1"}}
{"gene": "BDNF", "focus": "obesity_neurotrophic", "uniprot": {"gene": "BDNF", "status": "ok", "accession": "P23560", "entry": "BDNF_HUMAN", "protein_name": "Neurotrophic factor BDNF precursor form", "function": "Important signaling molecule that activates signaling cascades downstream of NTRK2 (PubMed:11152678). During development, promotes the survival and differentiation of selected neuronal populations of the peripheral and central nervous systems. Participates in axonal growth, pathfinding and in the modulation of dendritic growth and morphology. Major regulator of synaptic transmission and plasticity at adult synapses in many regions of the CNS. The versatility of BDNF is emphasized by its contribution to a range of adaptive neuronal responses including long-term potentiation (LTP), long-term depression (LTD), certain forms of short-term synaptic plasticity, as well as homeostatic regulation of intrinsic neuronal excitability Important signaling molecule that activates signaling cascades downstream of NTRK2. Activates signaling cascades via the heterodimeric receptor formed by NGFR and SORCS2 (PubMed:24908487, PubMed:29909994). Signaling via NGFR and SORCS2 plays a role in synaptic plasticity and long-term depression (LTD). Binding to NGFR and SORCS2 promotes neuronal apoptosis. Promotes neuronal growth cone collapse (By similarity)", "disease": ""}, "pubmed": {"gene": "BDNF", "status": "ok", "articles": [{"pmid": "42278442", "title": "Tail-Suspension Model of Simulated Microgravity-Induced Functional Dyspepsia in Rats: Behavioral, Motility, and Brain-Gut Peptide Alterations.", "journal": "International journal of molecular sciences", "year": "2026", "abstract": "Animal models are essential for elucidating human disease mechanisms and advancing translational research. Here, we used a well-established rat tail-suspension model to investigate the pathophysiological changes associated with simulated microgravity-induced functional dyspepsia (FD) and to evaluate its utility for preclinical to clinical translation. Thirty male Wistar rats were randomly assigned to control, simulated weightlessness using hindlimb unloading (HU), and domperidone groups. The HU model was induced by 21-day tail suspension, a widely accepted ground-based platform for simulating microgravity. Behavioral tests (sucrose preference, novelty-suppressed feeding), gastrointestinal motility measurements (gastric emptying, intestinal propulsion), and serum brain-gut peptide levels were assessed. Gastric and hypothalamic gene expression was analyzed by qRT-PCR. The model successfully recapitulated key FD phenotypes, including anxiety/depression-like behaviors, reduced gastric emptying and intestinal propulsion, and systemic brain-gut peptide imbalance-characterized by decreased excitatory peptides [substance P (SP), gastrin (GAS), motilin (MTL), ghrelin] and increased inhibitory peptides [vasoactive intestinal peptide (VIP), cholecystokinin (CCK), calcitonin gene-related peptide (CGRP), nesfatin-1] in serum. Consistent transcriptional dysregulation was observed in gastric and hypothalamic tissues. Hippocampal brain-derived neurotrophic factor (BDNF) was decreased, and colon 5-hydroxytryptamine (5-HT) increased, with no organic gastric lesions. Domperidone treatment significantly ameliorated behavioral abnormalities and gastrointestinal dysmotility, partially reversed brain-gut peptide imbalances at both protein and transcriptional levels, and restored hippocampal BDNF. These findings demonstrate that the rat tail-suspension model provides a reproducible platform for studying microgravity-induced FD, implicating brain-gut axis dysregulation. Domperidone's therapeutic effects highlight the model's utility for evaluating countermeasures against spaceflight-associated digestive dysfunction."}, {"pmid": "42278308", "title": "Humanised Environmental Enrichment: Spatial Effects of Cities and Buildings on Adult Hippocampal Neurogenesis in Humans.", "journal": "International journal of molecular sciences", "year": "2026", "abstract": "Adult hippocampal neurogenesis persists throughout the human lifespan, yet declines in Alzheimer's disease and major depression, associated in part with reduced brain-derived neurotrophic factor (BDNF) levels. For rodents, environmental enrichment, dichotomised primarily as physical activity and spatial complexity, robustly promotes adult hippocampal neurogenesis, but no framework has translated these findings to human environments. This review is the first to synthesise evidence across the full translational pathway, arguing that spatial complexity and physically active navigation in neighbourhoods and buildings constitute a humanised form of environmental enrichment. It proposes that standard indoor environments may represent a functionally impoverished condition for the human hippocampus, paralleling standard laboratory caging. An applied model is presented, mapping built environment features onto the neurobiological mechanisms regulating adult hippocampal neurogenesis, with BDNF as the central translatable biomarker linking environmental exposures to neurogenic outcomes. A methodological roadmap for future empirical validation is also outlined. This framework repositions the built environment as a modifiable determinant of adult hippocampal neurogenesis in humans, with implications for mitigating the risk of depression, cognitive impairment, and Alzheimer's disease."}, {"pmid": "42268366", "title": "Unlocking Neuroprotection: Exercise-Induced Muscle Secretome (Myokines) as a Therapeutic Avenue Against Alzheimer's Disease Pathogenesis.", "journal": "Journal of molecular neuroscience : MN", "year": "2026", "abstract": "This review critically evaluates exercise-induced myokines as neuroprotective agents against Alzheimer's disease (AD) and is structured around three thematic sections: (1) mechanistic foundations of myokine neuroprotection, (2) translational barriers to therapeutic development, and (3) a strategic framework for future research. Epidemiological studies associate physical exercise with reduced AD risk (30-45%), yet mechanisms remain incompletely resolved. Preclinical studies demonstrate that exercise-induced myokines (Irisin, BDNF, Cathepsin B) modulate AD pathology by: (1) attenuating amyloid-beta (A\u03b2)/tau accumulation, (2) suppressing neuroinflammation, and (3) enhancing synaptic plasticity. However, human exercise interventions show conflicting results influenced by APOE genotype, age, and exercise modality. Associative human data suggest that Interleukin-6 (IL-6) exemplifies pleiotropy-affording neuroprotective effects in acute contexts but potentially detrimental effects in states of chronic inflammation. Therapeutic hurdles include blood-brain barrier (BBB) penetration, pleiotropic risks, and patient heterogeneity. Emerging concepts such as combinatorial approaches (nanocarriers, exercise mimetics) and biomarker-driven trials are proposed as hypothetical future strategies; however, these remain unvalidated and require substantial preclinical development before implemented in clinical care. This narrative review is structured around three thematic sections: mechanistic foundations of myokine neuroprotection, translational barriers to therapeutic development, and a strategic framework for future research. The muscle-brain axis represents a compelling but complex therapeutic target. Based on current preclinical and correlational human evidence, future research should prioritize mechanistic rigor, standardized biomarker validation, and clinically viable delivery strategies. Notably, several approaches discussed herein-including nanocarrier delivery systems, exercise mimetics, and combinatorial myokine cocktails-remain speculative and are presented as future research directions rather than established therapeutic interventions."}, {"pmid": "42251712", "title": "Neuropsychopharmacological effects of Aronia melanocarpa: A narrative review.", "journal": "Psychiatria Danubina", "year": "2026", "abstract": "This narrative review examines the neuropsychopharmacological effects of Aronia melanocarpa (black chokeberry), focusing on its potential in the prevention and treatment of neuropsychiatric disorders such as anxiety, depression, and cognitive decline. A comprehensive literature search across Web of Science, Scopus, and Google Scholar identified 29 original studies, based on in vitro, animal, and human research. Findings demonstrated that Aronia melanocarpa, rich in polyphenols like anthocyanins and proanthocyanidins, exerts cognitive-enhancing, anxiolytic-like, and antidepressant-like effects. These outcomes are mediated by mechanisms involving antioxidant activity, modulation of neurotransmitter systems, inhibition of monoamine oxidases, reduction of neuroinflammation, modulation of gut microbiota, and upregulation of brain-derived neurotrophic factor (BDNF). Animal models of Alzheimer's disease and stress-induced disorders, along with human clinical trials, corroborated these effects. The review underscores the therapeutic promise of Aronia melanocarpa nutraceuticals in neuropsychiatric health and highlights the need for further clinical validation."}, {"pmid": "42239511", "title": "Unveiling the neuroprotective effects of pomegranate extract and/or physical activity against aluminum chloride-induced Alzheimer's disease in rats: modulation of multitude pathways.", "journal": "Frontiers in pharmacology", "year": "2026", "abstract": "Alzheimer's disease (AD) is a devastating neurodegenerative malady marked by cognitive dysfunction and increased deposition of amyloid-beta and hyperphosphorylated tau proteins. Aluminum-associated neurotoxicity is well-documented and manifests itself in the form of cognitive dysfunction. Nutraceuticals, such as pomegranate extract (POM) or physical activity (PHA), have been recognized to exert beneficial actions on human wellbeing. This study aimed to mechanistically scrutinize the effects of POM and PHA either separately or in combination on AlCl3-induced AD in rats. Sixty adult male Wistar rats were randomly assigned into five groups: control, AlCl3, AlCl3 + PHA, AlCl3 + POM, and AlCl3 + COMB (POM + PHA) and treated for 5\u00a0weeks. PHA and POM, either alone or in combination, exhibited a significant boost in memory and cognitive abilities, evidenced by the significant improvements in behavioral outcomes, elevations in monoamine (DA, NE, 5-HT), LRP1, and neprilysin levels, and reductions in acetylcholinesterase (ACHE) activity, APOE4 levels, and AD markers, relative to the AlCl3-intoxicated group. All treatments significantly ameliorated AlCl3-induced perturbations in antioxidant, neurotrophic, autophagic, inflammatory, endoplasmic reticulum (ER) stress, and apoptotic parameters, along with histopathological and immunohistochemical findings. These effects were demonstrated by the significant increase in antioxidant (Nrf2/HO-1/TAC/SOD), neurotrophic (PI3K/AKT/CREB/BDNF/TrKB), and autophagic (AMPK/SIRT-1/Beclin-1) markers, with significant reduction in neuroinflammatory (P38 MAPK/JNK/NF-\u03baB/JAK-2/STAT-3/TNF-\u03b1/IL-1\u03b2), ER stress (PERK/CHOP/GRP78), and apoptotic (BAX/P53/caspase-3) markers, relative to the AlCl3-intoxicated group. Interestingly, the combination exerted more favorable actions in all measured parameters and histological findings than the solo-treated groups. This study revealed the superiority of the combined therapy, compared to solo treatments, in alleviation of AlCl3-induced AD in rats, via adjustment of the Nrf2/HO-1, P38 MAPK/JNK/NF-\u03baB/JAK-2/STAT-3, PI3K/AKT/GSK-3\u03b2/CREB, AMPK/SIRT-1, PERK/CHOP, and apoptotic hubs."}]}, "alphafold": {"status": "ok", "uniprot": "P23560", "entry_id": "AF-P23560-F1", "uniprot_start": 1, "uniprot_end": 247, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P23560-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P23560-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P23560-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 236384, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P23560-F1.cif", "pdb_bytes": 162971, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P23560-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "BDNF"}}
{"gene": "BRCA1", "focus": "hereditary_cancer", "uniprot": {"gene": "BRCA1", "status": "ok", "accession": "P38398", "entry": "BRCA1_HUMAN", "protein_name": "Breast cancer type 1 susceptibility protein", "function": "E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage (PubMed:10500182, PubMed:12887909, PubMed:12890688, PubMed:14976165, PubMed:16818604, PubMed:17525340, PubMed:19261748). It is unclear whether it also mediates the formation of other types of polyubiquitin chains (PubMed:12890688). The BRCA1-BARD1 heterodimer coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability (PubMed:12890688, PubMed:14976165, PubMed:20351172). Regulates centrosomal microtubule nucleation (PubMed:18056443). Required for appropriate cell cycle arrests after ionizing irradiation in both the S-phase and the G2 phase of the cell cycle (PubMed:10724175, PubMed:11836499, PubMed:12183412, PubMed:19261748). Required for FANCD2 targeting to sites of DNA damage (PubMed:12887909). Inhibits lipid synthesis by binding to inactive phosphorylated ACACA and preventing its dephosphorylation (PubMed:16326698). Contributes to homologous recombination repair (HRR) via its direct interaction with PALB2, fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks (PubMed:19369211). Component of the BRCA1-RBBP8 complex which regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage via BRCA1-mediated ubiquitination of RBBP8 (PubMed:16818604). Acts as a transcriptional activator (PubMed:20160719)", "disease": ""}, "pubmed": {"gene": "BRCA1", "status": "ok", "articles": [{"pmid": "42277016", "title": "Spatiotemporal organisation of residual disease in mouse and human BRCA1-deficient mammary tumours and breast cancer.", "journal": "Nature communications", "year": "2026", "abstract": "Breast cancer remains a leading cause of death worldwide. Although chemotherapy reduces primary and metastatic tumour burden, persisting drug-tolerant tumour cell populations, known as minimal residual disease (MRD), pose a significant risk of recurrence and therapy resistance. In this study, we describe the spatiotemporal organisation of therapy response and MRD in BRCA1;p53-deficient mouse mammary tumours and human clinical samples. By integrating single-cell RNA sequencing, spatial transcriptomics, and imaging mass cytometry across multiple treatment timepoints, we characterise dynamic interactions between tumour cell subpopulations and their surrounding microenvironment. Our multiomic analysis uncovers a distinct, chemotherapy-tolerant epithelial-mesenchymal transition (EMT) cancer cell population that displays a conserved expression programme in human BRCA1-deficient tumours, significantly correlates with adverse clinical outcomes, and can be pharmacologically targeted in preclinical models. We reveal the spatial distribution of residual EMT-like tumour cells within discrete anatomical niches, providing a framework for understanding the persistence of MRD and potential therapeutic vulnerabilities."}, {"pmid": "42242799", "title": "An instrument-free height readout biosensing device based on gold nanobipyramid-loaded hydrogel for point-of-care detection of acid phosphatase and the BRCA1 gene.", "journal": "Analytica chimica acta", "year": "2026", "abstract": "Point-of-care testing (POCT) is crucial for disease diagnosis, especially in resource-limited settings with inadequate laboratory infrastructure. Although visual distance-based readout sensors present a promising approach for instrument-free quantification, their widespread application is hindered by complex fabrication processes and dependence on external driving mechanisms. Here we developed a universal, instrument-free visual quantification platform based on a gold nanobipyramid -loaded agarose (AuNBP/agarose) hydrogel encapsulated in a polycarbonate (PC) tube. The iodine-mediated etching of AuNBPs transduced target recognition into a measurable color-changing hydrogel height. The addition of acid phosphatase (ACP) initiated the enzymatic production of ascorbic acid (AA), driving the etching process and generated a height signal proportional to ACP concentration in the range of 0.1-1000 mU/mL, with a detection limit of 9.72 \u03bcU/mL. Moreover, it exhibited high selectivity and satisfactory recoveries for ACP in human serum samples. For DNA detection, target hybridization introduced horseradish peroxidase (HRP), which effectively inhibited etching by consuming H2O2. This strategy enabled sensitive detection of the BRCA1 gene within a concentration range of 100-1500\u202fnM, with a detection limit of 270\u202fnM. Both assays enabled quantitative readout using a simple ruler, without the need for complex instrumentation, demonstrating a universal and cost-effective strategy for POCT detection."}, {"pmid": "42219967", "title": "Microplastics as a Cross-Disease Driving Risk Factor in Lung Pathogenesis: An Integrative Study Combining In Silico Analysis and Experimental Validation Using Polystyrene Nanoplastics.", "journal": "Journal of applied toxicology : JAT", "year": "2026", "abstract": "Microplastics (MPs), as environmental pollutants, have garnered widespread attention. Growing evidence suggests a close association between MP exposure and lung diseases. However, the molecular mechanisms through which MP exposure influences the onset and progression of lung diseases remain unclear. This study positions MP exposure as a cross-disease driving risk factor and employs integrated computational toxicology and bioinformatics approaches to explore potential key targets underlying the impact of MP exposure on the development of lung diseases (COPD, IPF, and LUAD). Common differentially expressed genes (cDEGs) and shared common DEGs (scDEGs) associated with MP exposure and COPD, IPF, and LUAD were identified through database screening and intersection analysis. A protein-protein interaction (PPI) network was constructed using the STRING database, followed by enrichment analysis. The expression patterns and cellular localization of key targets among the shared common differentially expressed genes were validated using single-cell datasets of COPD, IPF, and LUAD. Finally, experimental validation was conducted based on the cell types identified through analysis. MP exposure may influence the occurrence and progression of COPD, IPF, and LUAD through mechanisms involving the cell cycle, mitosis, and DNA repair. Potential key targets identified include CDK1, BRCA1, and CCND1. Validation via database and single-cell analyses suggests that MP exposure may increase the risk of COPD, IPF, and LUAD by upregulating CDK1 expression in pulmonary fibroblasts. Experimental validation in human pulmonary fibroblasts demonstrated that PS-NPs significantly upregulated CDK1 mRNA and protein levels in a dose-dependent manner. CDK1 inhibition experiments confirmed that PS-NP exposure promotes fibrosis in human pulmonary fibroblasts by upregulating CDK1. This study defines MP exposure as a cross-disease driving risk factor and identifies CDK1 as a potential key target mediating the development of MPs-driven lung diseases. This finding offers a new perspective for understanding MPs-related lung diseases and establishes a novel paradigm for exploring the intrinsic connections between pollutant exposure and disease pathogenesis."}, {"pmid": "42193022", "title": "Genomic Biomarkers for First-Line Treatment Selection in Metastatic Pancreatic Ductal Adenocarcinoma: A Narrative Review.", "journal": "Cancers", "year": "2026", "abstract": "Metastatic pancreatic ductal adenocarcinoma (PDAC) is typically treated with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel (GnP), but the choice between regimens remains largely empirical. This narrative review summarizes biomarkers with potential to inform first-line selection in metastatic PDAC, emphasizing genomic and transcriptomic correlates of differential benefit. Recent head-to-head trials, particularly Pancreatic Adenocarcinoma Signature Stratification for Treatment (PASS-01) and GENERATE (Japan Clinical Oncology Group [JCOG] 1611), indicate that modified FOLFIRINOX (mFOLFIRINOX) is not uniformly superior to GnP, strengthening the rationale for biomarker-guided selection. The strongest evidence favoring platinum-based/FOLFIRINOX strategies involves homologous recombination repair deficiency (HRD), especially alterations in germline breast cancer gene 1/2 (BRCA1/2) or partner and localizer of BRCA2 (PALB2), as well as broader genomic scar signatures. Transcriptomic subtype and GATA-binding protein 6 (GATA6) expression are promising but remain unsettled because retrospective data favor classical/GATA6-high disease for FOLFIRINOX, whereas PASS-01 suggested better outcomes with GnP in classical tumors. Candidate biomarkers favoring GnP include high human equilibrative nucleoside transporter 1 (hENT1), low class III \u03b2-tubulin (TUBB3) expression, and exploratory phosphatidylinositol 3-kinase (PI3K)/KIT/NOTCH pathway mutation signals. Comprehensive molecular profiling also identifies actionable alterations that may redirect patients to targeted therapy or clinical trials rather than standard chemotherapy alone. Importantly, no biomarker has yet been prospectively validated in a biomarker-stratified randomized trial with regimen selection as the primary endpoint; all biomarker-regimen associations described in this review should therefore be considered hypothesis-generating rather than practice-defining. Nevertheless, the convergence of genomic, transcriptomic, and organoid-based approaches makes biologically informed first-line selection increasingly feasible in metastatic PDAC."}, {"pmid": "42191708", "title": "Allosteric network of dynamic coupling within BAP1-UCH revealed by methyl NMR.", "journal": "Nature communications", "year": "2026", "abstract": "BRCA1-associated protein 1 (BAP1) is a tumor suppressor whose deubiquitinase (DUB) activity is essential for transcriptional regulation and is frequently compromised in cancer by mutations clustered in its ubiquitin carboxyl-terminal hydrolase (UCH) domain. The structural and dynamic bases of these oncogenic mutations remain elusive. Here, we introduce 22 cancer mutations and additional methyl mutations on the other 22 cancer mutation sites of BAP1-UCH to map their effects on the methyl chemical shifts. This analysis reveals an allosteric coupling network centered on a conserved leucine (L49) shared across human UCH paralogs. Strikingly, a single-carbon side-chain truncation in the L49V variant abolishes DUB activity, coinciding with disruption of correlated \u03bcs-ms timescale motions within a phenylalanine cluster that undergoes concerted motions within the L49 hub. These findings uncover how BAP1-UCH sustains its catalytic competence through a delicately tuned dynamic network and how minute alterations can collapse this allosteric balance, providing a mechanistic link between subtle structural perturbations and oncogenesis."}]}, "alphafold": {"status": "ok", "uniprot": "P38398", "entry_id": "AF-P38398-F1", "uniprot_start": 1, "uniprot_end": 1863, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P38398-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P38398-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P38398-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 1725228, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P38398-F1.cif", "pdb_bytes": 1194182, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P38398-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "BRCA1"}}
{"gene": "BRCA2", "focus": "hereditary_cancer", "uniprot": {"gene": "BRCA2", "status": "ok", "accession": "P51587", "entry": "BRCA2_HUMAN", "protein_name": "Breast cancer type 2 susceptibility protein", "function": "Tumor suppressor protein that maintains genome stability primarily by repairing damaged DNA through homologous recombination (HR) (PubMed:11239456, PubMed:12442171, PubMed:15115758, PubMed:15199141, PubMed:15671039, PubMed:15937124, PubMed:17515903, PubMed:17515904, PubMed:18317453, PubMed:19303847, PubMed:20729832, PubMed:20729858, PubMed:20729859, PubMed:21719596, PubMed:27941124, PubMed:37499663, PubMed:37515771). Facilitates the repair of double-strand breaks (DSBs) by binding and mediating the loading of the RAD51 protein onto single-stranded DNA (ssDNA), thereby promoting the activity of RAD51, which catalyzes DNA strand exchange (PubMed:11239456, PubMed:12442171, PubMed:15937124, PubMed:17515903, PubMed:17515904, PubMed:18317453, PubMed:19303847, PubMed:20729832, PubMed:20729858, PubMed:20729859, PubMed:27941124, PubMed:37499663). BRCA2 nucleates and stabilizes RAD51 on ssDNA directly and delivers RAD51 to ssDNA-double-stranded DNA (dsDNA) junctions by sliding along dsDNA backbone (PubMed:12442171, PubMed:19303847, PubMed:37499663). RAD51 targeting to ssDNA promotes removal of replication protein-A (RPA) from ssDNA and stabilization of RAD51-ssDNA filaments by blocking ATP hydrolysis (PubMed:20729859). May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with PALB2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity (PubMed:24485656). Required to prevent R-loop-associated DNA damage and thus transcription-associated genomic instability (PubMed:24896180). Silencing of BRCA2 promotes R-loop accumulation at actively transcribed genes in replicating and non-replicating cells, suggesting that BRCA2 mediates the control of R-loop associated genomic instability, independently of its known role in homologous recombination (PubMed:24896180). Also promotes RAD51 loading to telomeric regions, facilitating telomere replication and capping (PubMed:21076401). Also required for homologous recombination during meiosis by promoting the recruitment of RAD51 and DMC1 recombinases to meiotic DSB sites, enabling proper chromosome pairing and crossing over (PubMed:26976601). Also promotes homologous recombination by inactivating the FIGNL1-FIRRM complex to protect RAD51 filament from premature disassembly (PubMed:37515771). Together with NPM1, may also regulate centrosome duplication (PubMed:21084279)", "disease": ""}, "pubmed": {"gene": "BRCA2", "status": "ok", "articles": [{"pmid": "42277940", "title": "DNA-contact mutant p53 displaces BRCA2 from chromatin and drives R-loop-associated genome instability.", "journal": "Genome biology", "year": "2026", "abstract": "Mutations in the tumor suppressor p53 are among the most frequent events in human cancers. Mutant p53 acquires oncogenic activities beyond the loss of tumor suppressive function. However, how different mutation subtypes differ in their contributions to tumorigenesis remains incompletely understood. Through pan-cancer TCGA analysis, we find that patients with p53 DNA contact mutations exhibit worse clinical outcomes than those carrying conformational mutations. Mechanistically, we demonstrate that the DNA contact mutation p53-R273H forms aberrant condensates that sequester BRCA2 and displace it from chromatin, leading to R-loop accumulation and genomic instability. We further identify the DEAD-box helicase DDX3X as a critical factor required for BRCA2-dependent R-loop resolution. Pharmacological inhibition of DDX3X with RK-33 synergizes with the PARP inhibitor Olaparib, enhancing therapeutic efficacy in p53 DNA contact mutant cancer cells. Our study establishes a pathogenic axis through which the clinically aggressive p53 DNA contact mutations drive genomic instability by dislodging BRCA2 from chromatin and disrupting R-loop homeostasis. These findings\u00a0suggest\u00a0a\u00a0potential therapeutic avenue\u00a0for treating cancers harboring high-risk p53 DNA contact mutations."}, {"pmid": "42193022", "title": "Genomic Biomarkers for First-Line Treatment Selection in Metastatic Pancreatic Ductal Adenocarcinoma: A Narrative Review.", "journal": "Cancers", "year": "2026", "abstract": "Metastatic pancreatic ductal adenocarcinoma (PDAC) is typically treated with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel (GnP), but the choice between regimens remains largely empirical. This narrative review summarizes biomarkers with potential to inform first-line selection in metastatic PDAC, emphasizing genomic and transcriptomic correlates of differential benefit. Recent head-to-head trials, particularly Pancreatic Adenocarcinoma Signature Stratification for Treatment (PASS-01) and GENERATE (Japan Clinical Oncology Group [JCOG] 1611), indicate that modified FOLFIRINOX (mFOLFIRINOX) is not uniformly superior to GnP, strengthening the rationale for biomarker-guided selection. The strongest evidence favoring platinum-based/FOLFIRINOX strategies involves homologous recombination repair deficiency (HRD), especially alterations in germline breast cancer gene 1/2 (BRCA1/2) or partner and localizer of BRCA2 (PALB2), as well as broader genomic scar signatures. Transcriptomic subtype and GATA-binding protein 6 (GATA6) expression are promising but remain unsettled because retrospective data favor classical/GATA6-high disease for FOLFIRINOX, whereas PASS-01 suggested better outcomes with GnP in classical tumors. Candidate biomarkers favoring GnP include high human equilibrative nucleoside transporter 1 (hENT1), low class III \u03b2-tubulin (TUBB3) expression, and exploratory phosphatidylinositol 3-kinase (PI3K)/KIT/NOTCH pathway mutation signals. Comprehensive molecular profiling also identifies actionable alterations that may redirect patients to targeted therapy or clinical trials rather than standard chemotherapy alone. Importantly, no biomarker has yet been prospectively validated in a biomarker-stratified randomized trial with regimen selection as the primary endpoint; all biomarker-regimen associations described in this review should therefore be considered hypothesis-generating rather than practice-defining. Nevertheless, the convergence of genomic, transcriptomic, and organoid-based approaches makes biologically informed first-line selection increasingly feasible in metastatic PDAC."}, {"pmid": "42189716", "title": "Molecular architecture of the tumor microenvironment caused by ", "journal": "eLife", "year": "2026", "abstract": "Homologous recombination repair (HRR) deficiency is associated with improved immunotherapy responses in non-small cell lung cancer (NSCLC) patients. The HRR genes BRCA1/2 are key regulators of DNA repair, yet their impact on the tumor microenvironment (TME) in lung adenocarcinoma (LUAD) remains unclear. Using single-cell sequencing and multi-omics data, we characterized BRCA1/2 mutation-associated transcriptional programs, immune cell composition, and functional alterations in T cells, investigating the molecular and immune architecture of BRCA-mutant LUAD patients. BRCA1/2 mutations were associated with increased genomic instability and poor prognosis in LUAD patients, but predicted better clinical outcomes following immune checkpoint blockade (ICB) treatment. BRCA1 mutations correlated with an upregulated type I IFN/IFN-\u03b3 signature and CD8+ T cell activation. BRCA2 mutations were associated with alveolar/stress/inflammatory responses and enhanced MHC-II antigen presentation, linked to CD4+ T cell differentiation. Both alterations coincided with reduced CD28 co-stimulation and CTL activity, hinting at immune evasion. We identified two tissue-resident memory T cell (Trm) subsets as predictors of clinical outcomes and ICB response. BRCA1 mutations were associated with CD8+ Trm expansion, whereas BRCA2 mutations were linked to tumor CD4+ Trm expansion and peripheral T/NK cell cytotoxicity. Furthermore, a cancer-promoting program activated by BRCA1 mutation was vulnerable to histone deacetylase inhibitors, which inhibited LUAD tumor growth. This study provides a preliminary characterization of the BRCA-mutant TME in LUAD patients, revealing distinct transcriptional and immune patterns that highlight differences in BRCA1/2-associated molecular architecture and offer a framework for improving therapy efficacy in LUAD."}, {"pmid": "42183723", "title": "Adjuvant olaparib real world data for ", "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "year": "2026", "abstract": "IntroductionSince 2023 olaparib has been commissioned in the United Kingdom for breast cancer for patients with breast cancer gene 1 and 2 (BRCA1 and 2) positive, human epidermal growth factor receptor 2 (HER2)-negative, high-risk early disease after chemotherapy. Our study describes tolerability and adverse effects, to understand continued applicability of the OlympiA trial analyses through comparison to available real-world data.Materials and methodsThis was a retrospective observational study using secondary real-world data for 47 patients who received olaparib between April 2023 and March 2024 from 11 NHS and HSC hospitals. Anonymised data was collected from electronic patient records for eligible patients. A standardised data collection tool was utilised capturing key metrics. Statistical analysis included descriptive statistics and comparisons of adverse events with the OlympiA trial using Chi-square or Fisher's exact tests (p\u2009<\u20090.05).ResultsThe research sample at baseline had broader age range including patients in their 60s, compared to the OlympiA patient population which lacked those aged over 49. It also has a more even distribution of BRCA1/BRCA2 mutations, higher rates of hormone receptor positive HER2-negative cancers and a greater use of neoadjuvant and platinum-based treatments. Adverse events were similar between the two populations. Fatigue was significantly more prevalent compared to OlympiA (p\u2009<\u20090.05). Nineteen patients had dose reductions due to adverse effects and four patients discontinued treatment early.ConclusionAdjuvant olaparib was well tolerated in our real-world UK population study, with toxicity profiles similar to the OlympiA trial. Fatigue was significantly more prevalent in the real-world cohort."}, {"pmid": "42110911", "title": "Clinical variant interpretation comparing two saturation genome editing-based functional studies for ", "journal": "Frontiers in genetics", "year": "2026", "abstract": "Two saturation genome editing (SGE) studies for BRCA2 using haploid human HAP1 cells and mouse embryonic stem cells, respectively, demonstrated contradictory functional results in 16.9% (1,052/6,208) of the variants. We performed clinical variant interpretation and tried to address the discordance by comparing two studies combined with 24 years of clinicopathological data collected at a single institution. Retrospectively, we collected data from patients with BRCA2 variants evaluated in the SGE studies. The variants were reassessed according to the ClinGen BRCA1/2 guidelines and/or multifactorial likelihood analysis. For variants with concordant SGE functional results, either PS3 or BS3 was assigned. Major error rates were compared for variants with discordant results. Among the 88 variants from 526 patients, 13, including three potentially hypomorphic variants, showed discordant results. Major error rates were lower for HAP1-SGE dataset, but without statistical significance. Among the 75 variants with concordant results, 28 and 47 were assigned PS3 and BS3, respectively. Consequently, 93.1% (27/29) of the variants of uncertain significance were reclassified as likely pathogenic (n = 3) or likely benign (n = 24). Concordant SGE results are clinically useful for variant reclassification. When discordant results are present, functional evidence should not be assigned, but HAP1-SGE dataset is suggested to be more consistent with patient-specific data. Further segregation analysis and long-term follow-up are needed to resolve discordant cases."}]}, "alphafold": {"gene": "BRCA2", "uniprot": "P51587", "status": "error", "error": "<HTTPError 404: 'Not Found'>"}}
{"gene": "TP53", "focus": "hereditary_cancer", "uniprot": {"gene": "TP53", "status": "ok", "accession": "P04637", "entry": "P53_HUMAN", "protein_name": "Cellular tumor antigen p53", "function": "Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence (PubMed:11025664, PubMed:12524540, PubMed:12810724, PubMed:15186775, PubMed:15340061, PubMed:17317671, PubMed:17349958, PubMed:19556538, PubMed:20673990, PubMed:20959462, PubMed:22726440, PubMed:24051492, PubMed:24652652, PubMed:35618207, PubMed:36634798, PubMed:38653238, PubMed:9840937). Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type (PubMed:11025664, PubMed:12524540, PubMed:12810724, PubMed:15186775, PubMed:15340061, PubMed:17189187, PubMed:17317671, PubMed:17349958, PubMed:19556538, PubMed:20673990, PubMed:20959462, PubMed:22726440, PubMed:24051492, PubMed:24652652, PubMed:38653238, PubMed:9840937). Negatively regulates cell division by controlling expression of a set of genes required for this process (PubMed:11025664, PubMed:12524540, PubMed:12810724, PubMed:15186775, PubMed:15340061, PubMed:17317671, PubMed:17349958, PubMed:19556538, PubMed:20673990, PubMed:20959462, PubMed:22726440, PubMed:24051492, PubMed:24652652, PubMed:9840937). One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression (PubMed:12524540, PubMed:17189187). Its pro-apoptotic activity is activated via its interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 (PubMed:12524540). However, this activity is inhibited when the interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP (PubMed:12524540). In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seems to have an effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Regulates the circadian clock by repressing CLOCK-BMAL1-mediated transcriptional activation of PER2 (PubMed:24051492)", "disease": ""}, "pubmed": {"gene": "TP53", "status": "ok", "articles": [{"pmid": "42276825", "title": "Network pharmacology of Sijunzi decoction in pancreatic cancer.", "journal": "Chinese clinical oncology", "year": "2026", "abstract": "Sijunzi decoction (SJZD) is a traditional Chinese medicine (TCM) commonly used for pancreatic ductal adenocarcinoma (PDAC), but its mechanisms remain unclear. This study investigates its molecular basis using network pharmacology and molecular docking. Active compounds and targets of SJZD were identified via Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database and Analysis Platform, and PDAC-related targets were retrieved from Online Mendelian Inheritance in Man (OMIM) and GeneCards. Protein-protein interaction (PPI) networks, Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and tissue distribution analyses were conducted. Molecular docking evaluated binding affinities between compounds and targets. The anti-PDAC effects of SJZD were evaluated in vitro using human pancreatic cancer cell lines (CFPAC-1 and MiaPaCa-2) and in vivo using a patient-derived xenograft (PDX) mouse model. SJZD comprises 131 compounds and 260 targets, with key targets such as AKT serine/threonine kinase 1 (AKT1), BCL2 associated agonist of cell death (BAD), BCL2 apoptosis regulator (BCL2), and tumor protein p53 ( TP53) identified through PPI analysis. Enrichment analyses highlighted the phosphatidylinositide 3-kinases (PI3K)/protein Kinase B (AKT)/mechanistic target of rapamycin kinase (mTOR) and apoptosis pathways as primary therapeutic mechanisms. SJZD exhibited cytotoxic effects against PDAC cells in vitro and suppressed tumor growth in vivo, with mechanistic analyses confirming its regulatory effects on the PI3K/AKT/mTOR and apoptosis pathways. Molecular docking revealed strong binding affinities, particularly for compounds targeting estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2). These findings suggest that SJZD exerts anti-PDAC effects via multi-target modulation, primarily through inhibition of the PI3K/AKT/mTOR signaling axis, induction of apoptosis and autophagy, and anti-inflammatory activity. The involvement of classic compounds supports the rationale of its traditional use, while experimental validation provides a mechanistic foundation for future clinical development. This study clarifies the active components, targets, and mechanisms of SJZD in treating PDAC, offering insights into the therapeutic potential of TCM."}, {"pmid": "42276414", "title": "Predicting TP53 biomarkers from whole slide images across human solid tumours using weakly supervised learning.", "journal": "The American journal of pathology", "year": "2026", "abstract": "Accurate molecular profiling from routine histopathology slides could transform clinical oncology. A Vision Transformer (ViT)-based model was developed to jointly predict the TP53 biomarker, detect 32 solid tumour types, and predict survival directly from Whole Slide Images (WSIs). Over 11K primary tumour data were retrieved from the Pan-Cancer Atlas, along with corresponding somatic mutation, RNA-seq, and clinical outcome data. WSIs underwent tissue masking, quality control, stain normalisation, patch extraction, and feature embedding using a ViT encoder. Seven task heads were developed to generate predictions for cancer type, TP53 mutation status, TP53 RNA expression levels, overall survival, progression-free interval, and their corresponding event times. Model training proceeded in two stages: initial training on tumour-only patches at multiple magnifications, followed by fine-tuning on WSIs using a content-aware strategy. Model performance was evaluated on an independent validation set of 1,729 slides using evaluation metrics, including the area under the receiver operating characteristic curve (AUROC), regression metrics, and the concordance index. An AUROC of 0.766 for TP53 mutation detection on an independent validation set across 32 human solid tumours. In conclusion, the ViT-based model could simultaneously infer TP53 mutation status, TP53 RNA expression levels, and tumour taxonomy directly from WSIs, supporting the existence of reproducible morphologic correlates of TP53 alterations across human cancers, whereas prognostic risk prediction remained limited."}, {"pmid": "42269376", "title": "Rising incidence of oral tongue squamous cell carcinoma in young women: Emerging non-traditional etiologic factors and clinical implications: A structured narrative review.", "journal": "Cancer epidemiology", "year": "2026", "abstract": "Oral squamous cell carcinoma (OSCC) accounts for the majority of oral malignancies worldwide, with oral tongue squamous cell carcinoma (OTSCC) considered one of its most aggressive subtypes. Historically, OSCC has predominantly affected older males with substantial tobacco and alcohol exposure. However, emerging epidemiologic evidence demonstrates a rising incidence of OTSCC among young females, particularly patients aged \u2264\u202f45 years, many of whom lack these traditional risk factors, suggesting distinct etiologic pathways. A structured narrative review using a comprehensive literature search strategy was conducted using PubMed, Scopus, Ovid MEDLINE, and Web of Science, combining terms related to oral cancer, tongue, young patients aged \u2264\u202f45 years, females, incidence, and risk factors. Of 653 records identified, 19 studies met the inclusion criteria after exclusion of non-English articles, conference abstracts, animal studies, and non-oral tongue reports. Population-based and institutional data from North America, Europe, Asia, and Australia consistently report increasing OTSCC incidence among young women, in some regions surpassing rates observed in age-matched men. Many affected patients are non-smokers, non-drinkers, and human papillomavirus (HPV)-negative. Proposed non-traditional contributors include genetic susceptibility, family history of malignancy, hormonal influences, early-life carcinogen exposure, chronic mucosal irritation, metabolic comorbidities, environmental factors, and possible misclassification of HPV-related base-of-tongue tumors. Molecular findings suggest distinct patterns of TP53 alterations and chromosomal instability in younger patients. The growing burden of OTSCC in young women underscores the need for improved early detection and multi-institutional molecular studies to clarify mechanisms and inform tailored prevention and treatment strategies."}, {"pmid": "42258702", "title": "A pan-cancer single-cell analysis of intratumoral copy number diversity and evolution.", "journal": "Cancer discovery", "year": "2026", "abstract": "Aneuploidy is a hallmark of human tumors. While patient-level copy number alteration (CNA) differences have been investigated extensively in large cohorts, their intratumoral heterogeneity remains understudied. Here, we conducted a pan-cancer analysis of 94 human tumors at single cell resolution, representing seven cancer types: bladder, breast, colon, glioblastoma, kidney, lung, and ovarian. Single-cell copy number profiling was used to analyze 62,646 aneuploid cells, in addition to bulk exome sequencing of most patients and single-nucleus RNA-seq of 6 samples. In many cancer types, increased subclonal diversity was associated with higher CNA burden, whole genome doubling, TP53 mutations, and increased geographic diversity. Cancer cells from each patient shared a set of truncal CNAs, suggesting evolution from a single ancestral cell. Many tumors accumulated CNAs in bursts of evolution, suggesting that punctuated evolution is common in diverse cancer types. This study greatly improves our knowledge of intratumoral chromosome diversity across human cancers."}, {"pmid": "42249018", "title": "TP53 mutation at codon 179 metabolically reprograms cancer cells to promote invasion.", "journal": "Cancer gene therapy", "year": "2026", "abstract": "Mutations in the tumour suppressor, TP53, are prevalent in human cancers yet their functional implications remain unclear. Through comprehensive pan-cancer database analysis, we identified H179 mutations in TP53 as significantly associated with poor disease-free survival across multiple cancer types. Functional studies in lung, ovarian, and prostate cancer cells over-expressing the p53H179R/Y mutants revealed that these mutants are not only defective in tumour-suppressive functions but also actively promote tumour progression. These mutants drive metabolic reprogramming by increasing neutral lipid levels through de novo fatty acid synthesis (p53H179R/Y) and fatty acid uptake (p53H179Y), accompanied by increased lipid droplets and APOE expression, collectively promoting enhanced invasiveness relative to p53-null cells. Our findings demonstrate that TP53 missense mutations are not functionally equivalent to TP53 loss. Notably, H179 mutations act as oncogenic drivers, and our data highlight APOE and lipid metabolism as potential therapeutic targets, underscoring the clinical relevance of precise TP53 mutation characterisation."}]}, "alphafold": {"status": "ok", "uniprot": "P04637", "entry_id": "AF-P04637-F1", "uniprot_start": 1, "uniprot_end": 393, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P04637-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P04637-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P04637-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 363485, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P04637-F1.cif", "pdb_bytes": 254339, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P04637-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "TP53"}}
{"gene": "MLH1", "focus": "mismatch_repair_cancer", "uniprot": {"gene": "MLH1", "status": "ok", "accession": "P40692", "entry": "MLH1_HUMAN", "protein_name": "DNA mismatch repair protein Mlh1", "function": "Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis", "disease": ""}, "pubmed": {"gene": "MLH1", "status": "ok", "articles": [{"pmid": "42219787", "title": "Computational Analysis of Differentially Expressed Genes in Arsenic-Induced Carcinogenesis and Their Effect on Human Repair Mechanisms.", "journal": "Environmental and molecular mutagenesis", "year": "2026", "abstract": "Arsenic poisoning significantly elevates the risk of cancer and other chronic illnesses. The goal of this research is to identify important genes whose expression changes in response to arsenic toxicity, and the molecular pathways affected by arsenic, using computational analysis of arsenic toxicity profiles. This approach will computationally identify and analyze genes whose expression changes in response to arsenic, thereby elucidating the heightened risk of carcinogenesis in arsenic-exposed individuals. This work employed high-throughput arsenic toxicity profiles to computationally identify and analyze expressed genes (DEGs) differentially in Affymetrix microarray datasets from the Gene Expression Omnibus (GEO) database, which were screened using the GEO2R program. A protein-protein interaction (PPI) network was constructed using STRING to elucidate the functional links between these DEGs and DNA repair genes. Interactions between the seven central genes (E2F1, EXO1, EZH2, FEN1, HIST1H3A, POLA1, and TIMELESS) and the repair genes PARP1, NBN, PMS1, MSH3, XRCC5, XRCC6, MGMT, and MLH1 were discovered. We employed the DAVID and Enrichr-KG platforms to investigate the functions of these genes and their associations with cellular and molecular processes in greater detail. Two hundred eighty-one non-synonymous single-nucleotide polymorphisms (nsSNPs) in the 07 genes linked to arsenic toxicity were found using the COSMIC database. Based on our analysis, mutations in E2F1, EXO1, EZH2, FEN1, HIST1H3A, POLA1, and TIMELESS can hinder DNA repair mechanisms, ultimately leading to cancer. Our computational analysis demonstrated that these non-synonymous SNPs can affect gene function, potentially altering protein stability and activity. Furthermore, according to Metal-Protein docking and protein-protein docking, these genes and their mutations appear to affect interactions with repair proteins substantially. Specific dietary consumption may lessen the detrimental effects of arsenic poisoning on protein function. We hypothesized that the mutations might be reversed by attaching particular molecules to these mutants. The protective effects of six curcumin compounds were examined using molecular docking with AutoDock 4.2.6 to assess protein dynamics and binding interactions. Optimal complexes were selected for dynamics simulation using GROMACS, and potential strategies for long-term cancer prevention related to arsenic exposure were identified."}, {"pmid": "42018405", "title": "Mechanism of MutL\u03b2-dependent DNA expansions.", "journal": "Proceedings of the National Academy of Sciences of the United States of America", "year": "2026", "abstract": "MutS and MutL proteins and their eukaryotic homologs have important functions in DNA metabolism. MutL\u03b2 (MLH1-PMS1 heterodimer) is a poorly understood eukaryotic MutL complex. Recent genetic studies have implicated MutL\u03b2 in the process of expansion of the short, tandem DNA repeat tracts that is responsible for the repeat expansion diseases. The function of MutL\u03b2 and the mechanism of MutL\u03b2-dependent DNA expansions have not been established. We show here that MutL\u03b2 promotes MutS\u03b2- and MutL\u03b3-dependent DNA expansions in human cell extracts and defined systems. Importantly, DNA expansions that occur in human cell extracts in the presence of MutS\u03b2 and a low concentration of MutL\u03b3 require MutL\u03b2. A MutS\u03b2 variant lacking the PCNA-binding motif is proficient in supporting MutL\u03b2-promoted and MutL\u03b3-dependent DNA expansions. We also show that MutL\u03b2 enhances the MutS\u03b2-dependent endonuclease activity of MutL\u03b3 that incises the loop-lacking strand of loop-containing DNAs. MutL\u03b2 also increases the endonuclease activity of MutL\u03b3 in the presence of ATP-Mn2+ and physically interacts with MutL\u03b3, MutS\u03b2, and PCNA. In addition, MutL\u03b2 suppresses inhibition of DNA expansion by MutS\u03b1. An MLH1-F80V substitution in MutL\u03b2 causes a defect in the ability of the protein to promote MutS\u03b2- and MutL\u03b3-dependent DNA expansions. Taken together, our findings support a model in which MutL\u03b2 is involved in DNA expansions by acting in a MutS\u03b2- and MutL\u03b3-dependent mechanism that includes incision of loop-containing DNAs in the loop-lacking strand."}, {"pmid": "41808208", "title": "Targeted native long-read sequencing of DNA methylation alterations following CRISPR-Cas9-induced double-strand breaks in human cells.", "journal": "BMC research notes", "year": "2026", "abstract": "CRISPR-Cas9 nucleases are widely used to introduce targeted DNA double-strand breaks (DSBs) for genome engineering, but the long-term impact of these lesions on local epigenetic information remains poorly characterized. In a companion research article, we used Cas9-assisted targeted nanopore sequencing (CTS) to reveal that CRISPR-Cas9-induced DSBs can disrupt local epigenetic maintenance across multiple genomic contexts and cell systems. Here, we present a structured description of the raw and minimally processed datasets underlying the study. These datasets provide base-resolution measurements of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) at the differentially methylated regions (DMRs) of several imprinted loci, two heterochromatic regions, a cancer-associated promoter epimutation region, and the SNRPN DMR at early/late passages of a clonal line. They enable re-analysis and methodological benchmarking of DSB-associated epigenetic instability. We provide aligned BAM files and per-CpG methylation calls for multiple genomic contexts under both CRISPR-targeted and non-targeting control conditions. Specifically, the collection includes: (i) imprinted loci in human embryonic stem cells (hESCs), including small nuclear ribonucleoprotein polypeptide N (SNRPN), paternally expressed 10 (PEG10), and KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1), (ii) heterochromatic regions in hESCs, including urothelial cancer associated 1 (UCA1), and cysteine rich C-terminal 1 (CRCT1)), (iii) the epimutation locus of MutL homolog 1 (MLH1) in RKO cells, and (iv) the DMR of SNRPN locus in early- and late-passage derivatives of a single hESC clone. For each collection, there is a dataset that includes both the raw aligned Nanopore sequencing reads (BAM) deposited in the NCBI Sequence Read Archive (SRA) and the corresponding processed per-CpG 5mC/5hmC matrices deposited in Zenodo. All higher-level analyses in the research article-such as DMR calling, haplotype-resolved analyses, and structural variant (SV) characterization-are fully reproducible using these deposited data. Additional processed analyses are comprehensively documented in the companion article and are therefore not duplicated here. Together, these datasets offer a rich resource for benchmarking long-read methylation analysis workflows and further investigation of DSB-associated epigenetic instability across diverse genomic contexts."}, {"pmid": "41543911", "title": "An accurate cellular assay to determine pathogenicity of coding and noncoding variants in Lynch syndrome genes.", "journal": "Proceedings of the National Academy of Sciences of the United States of America", "year": "2026", "abstract": "Lynch syndrome (LS) is a genetic predisposition to mainly colorectal and endometrial cancer due to heterozygous disruptive germline mutations in the DNA mismatch-repair (MMR) genes MSH2, MSH6, MLH1, or PMS2. Beyond clearly pathogenic mutations, germline sequencing often reveals variants of uncertain significance (VUS), predominantly single base-pair alterations in coding or noncoding regions. These uncertain variants obstruct LS diagnosis, hampering personalized surveillance. To address this challenge, we developed a highly accurate functional assay that interrogates VUS pathogenicity in human cells. Building on a mouse-based cellular assay, we adapted oligonucleotide-directed mutation screening (ODMS) for human cells and introduced a refined approach named \"coselection ODMS.\" To ensure physiological expression, the variant is introduced into the endogenous MMR gene by replication-coupled gene editing. Coselection ODMS demonstrated 100% accuracy in classifying 50 benign and 86 pathogenic variants spanning coding and noncoding regions in all four MMR genes. Among 109 patient-derived VUS, 51 were identified as deleterious for MMR function. Importantly, coselection ODMS delivered 100% concordant results in a clinical diagnostic laboratory. With >93% sensitivity and >92% specificity, coselection ODMS provides a highly reliable functional assay in the diagnosis of enigmatic LS variants, enabling risk assessment and personalized surveillance or treatment for affected families."}, {"pmid": "41439704", "title": "DNA mismatch repair mediated by Mlh1-Pms1 endonuclease-catalyzed mispair excision.", "journal": "Proceedings of the National Academy of Sciences of the United States of America", "year": "2025", "abstract": "Eukaryotic DNA mismatch repair (MMR) involves several excision pathways, including those mediated by exonuclease 1 (Exo1) and by the flap endonuclease Rad27 (human FEN1) coupled with DNA polymerase \u03b4. Simultaneous inactivation of both excision mechanisms causes an MMR defect that is at most 5 to 13% of that caused by complete inactivation of MMR. Here, we reconstituted nicked-strand-specific MMR with the Saccharomyces cerevisiae proteins Msh2-Msh6 or Msh2-Msh3, DNA polymerase \u03b5, RFC, PCNA, RPA, and Mlh1-Pms1 (human Mlh1-Pms2) under conditions lacking Exo1, Rad27, or strand-displacement synthesis by DNA polymerase \u03b4. These reactions required the Mlh1-Pms1 endonuclease activity, its activation by RFC and PCNA, and its recruitment by Msh2-Msh6 or Msh2-Msh3. MMR was mediated by nicked-strand-specific excision by Mlh1-Pms1 through formation of single-strand DNA gaps having a broad range of sizes. This reaction is consistent with genetic data demonstrating redundancy between the Exo1, Rad27, and Mlh1-Pms1 excision pathways in MMR."}]}, "alphafold": {"status": "ok", "uniprot": "P40692", "entry_id": "AF-P40692-F1", "uniprot_start": 1, "uniprot_end": 756, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P40692-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P40692-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P40692-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 691988, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P40692-F1.cif", "pdb_bytes": 490454, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P40692-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "MLH1"}}
{"gene": "LDLR", "focus": "lipid_metabolism", "uniprot": {"gene": "LDLR", "status": "ok", "accession": "P01130", "entry": "LDLR_HUMAN", "protein_name": "Low-density lipoprotein receptor", "function": "Binds low density lipoprotein /LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. Forms a ternary complex with PGRMC1 and TMEM97 receptors which increases LDLR-mediated LDL internalization (PubMed:30443021) (Microbial infection) Acts as a receptor for hepatitis C virus in hepatocytes, but not through a direct interaction with viral proteins (Microbial infection) Acts as a receptor for Vesicular stomatitis virus (Microbial infection) In case of HIV-1 infection, may function as a receptor for extracellular Tat in neurons, mediating its internalization in uninfected cells (Microbial infection) Acts as a receptor for Crimean-Congo hemorrhagic fever virus (CCHFV) (Microbial infection) Acts as a receptor for many Alphavirus, including Getah virus (GETV), Ross river virus (RRV) and Semliki Forest virus", "disease": ""}, "pubmed": {"gene": "LDLR", "status": "ok", "articles": [{"pmid": "42265108", "title": "LRP4 is an entry receptor for multiple encephalitic alphaviruses.", "journal": "Nature communications", "year": "2026", "abstract": "Encephalitic alphaviruses, including Eastern equine encephalitis virus (EEEV), cause severe neurological disease with high mortality rates, and thus are a public health threat. Although members of the low-density lipoprotein receptor (LDLR) family, including VLDLR, LRP8 (ApoER2), and LDLR recently were identified as receptors for EEEV, residual infection in receptor-deficient cells suggests that additional entry factors exist. Using a CRISPR-based activation screen, we identified LDLR-related protein 4 (LRP4) as a candidate entry factor for EEEV and several related alphaviruses (Western equine encephalitis, Semliki Forest, and Sindbis viruses). LRP4 mediates viral attachment and internalization, and its ligand-binding domain binds directly to virions. Soluble LRP4 decoy proteins potently inhibit EEEV infection in primary mouse neuronal cells, male mice, and human brain organoids, suggesting possible therapeutic applications. Mammalian and avian LRP4 orthologs demonstrate conserved functions in promoting EEEV infection, supporting a possible role in its host range of infection and transmission. Our findings establish LRP4 as a shared entry receptor for multiple alphaviruses and expand our understanding of alphavirus tropism, pathogenesis, and countermeasure development."}, {"pmid": "42177120", "title": "NOD1 ligand FK565 promotes atherogenesis and accumulation of NOD1", "journal": "Atherosclerosis", "year": "2026", "abstract": "Nucleotide-binding oligomerization domain-containing protein (NOD)1 is an intracellular pattern recognition receptor that initiates immune responses upon ligation of molecules such as bacterial peptidoglycan containing a D-glutamyl-meso-diaminopimelic acid (iE-DAP) moiety. NOD1 ligation has been shown to promote vascular inflammation and atherosclerosis. In this study, we investigate the functional role of NOD1 in atherosclerotic plaques and characterize the vascular cells responsible for NOD1 expression and function. NOD1 was mainly expressed in a subtype of vascular smooth muscle cells (SMC) in human atherosclerotic lesions. In ex vivo cultures, human endarterectomy specimens reacted to NOD1 ligand by activation of mitogen-activated protein kinase (MAPK) p38 pathway, leading to cytokine expression. Levels of NOD1 mRNA were higher in carotid endarterectomy specimens obtained from symptomatic patients compared to asymptomatic ones. NOD1+ SMC were also found in arteries of atherosclerosis-prone Ldlr-/- mice. Challenging these mice with a NOD1 agonist resulted in transmural vascular inflammation, severe arterial damage, accelerated atherogenesis throughout the aorta, and evidence of occlusive coronary artery disease. In rats, mechanic injury to carotid arteries promoted NOD1+ SMC expansion and neointima formation. In vitro, neointima derived NOD1+ SMCs responded to NOD1 ligand exposure by enhanced migration, increased iNOS+ cells and amplified CCL5 production. Our findings show that NOD1 promotes vascular inflammation, vascular injury responses and atherosclerosis by acting on a NOD1+ subtype of SMC."}, {"pmid": "42168212", "title": "Flow-mediated endothelial remodeling and inflammation drive developmental vascular susceptibility in ldlr loss of function.", "journal": "Nature communications", "year": "2026", "abstract": "Atherosclerosis, the leading cause of cardiovascular disease, is associated with aberrant lipid metabolism, endothelial dysfunction, and chronic inflammation, yet its early manifestations and mechanisms remain incompletely understood. As low-density lipoprotein receptor loss of function is the most common monogenic cause of atherosclerosis, we employed low-density lipoprotein receptor knockout (ldlr-/-) zebrafish to investigate the developmental origins of atherosclerotic cardiovascular disease. Single-cell RNA-sequencing under differential flow conditions in embryonic ldlr-/- zebrafish identified a population of disproportionately stressed endothelial cells marked by overexpression of heat shock protein 70 (hsp70). Hsp70 is induced in stressed endothelial cells in a flow-dependent manner in zebrafish and a subset of human endothelial cells, and its activation is associated with disrupted remodeling angiogenesis in vivo. Genetic and pharmacological studies demonstrated that hsp70 upregulation inhibits vascular apoptosis and ciliogenesis, leading to altered angiogenic remodeling. Concurrently, pro-inflammatory processes, including enhanced myelopoiesis and thrombogenicity, are amplified at early stages in ldlr-/- zebrafish, which also exhibit impaired regenerative angiogenesis and heightened neutrophil recruitment post-vascular injury. Our findings reveal how abnormalities in flow-mediated endothelial remodeling and inflammation converge during embryogenesis to drive vascular susceptibility to hemodynamic and other stressors in ldlr loss of function."}, {"pmid": "42165151", "title": "Macrophage EHD1 Promotes Inflammation and Stabilizes Sortilin to Accelerate Atherosclerosis.", "journal": "Circulation research", "year": "2026", "abstract": "Macrophages are key players in the pathogenesis of atherosclerosis. They trigger immune responses through their cell-surface receptors. However, how macrophages regulate those receptors in response to proinflammatory stimuli is not completely understood. Endocytic membrane trafficking involving receptor internalization, followed by endosomal transport and recycling of the internalized receptors, plays essential roles in balancing cell-surface receptors to meet cellular needs. Here, we explored the role of the endocytic regulator EHD (c-terminal Eps15 homology domain) 1 in immune responses in macrophages and determined its contribution to atherosclerosis progression. EHD1 expression profiles in mouse and human plaques were determined by single-cell RNA sequencing and immunofluorescence staining. Bone marrow transplantation by transplanting bone marrow cells from Ehd1-/- or littermate wild-type mice to irradiated Ldlr-/- mice was performed to determine the effect of EHD1 deletion on atherosclerosis progression. In vitro mechanistic studies, including inflammation signaling and endocytosis assays, were performed in bone marrow-derived macrophages. EHD1 expression in macrophages is enhanced as atherosclerosis progresses in both mice and humans. Histological analysis of aortic root sections from bone marrow transplantation mice showed that EHD1 deletion reduces lesion size. Single-cell RNA sequencing of aortic CD (cluster of differentiation) 45+ cells demonstrated that EHD1 deletion attenuates proinflammatory responses and cell-cell interactions. Mechanistic studies revealed that EHD1 accelerates the endocytic recycling of TNFR2 (tumor necrosis factor receptor 2) and activates NF-\u03baB (nuclear factor kappa B), leading to increased expression of inflammatory cytokines. Moreover, EHD1 interacts with retromer and stabilizes sortilin, a retrograde cargo of retromer and a risk factor for atherosclerosis. EHD1 promotes inflammation by enhancing TNFR2-NF-\u03baB signaling and stabilizing sortilin, leading to accelerated atherosclerosis. Our study reveals novel roles for EHD1-mediated membrane trafficking in macrophage function and paves the way to innovative therapeutic strategies that aim to address dysregulated membrane trafficking in atherosclerosis."}, {"pmid": "42131916", "title": "Perk Is Dispensable for Smooth Muscle Cell Phenotype Switching in Atherosclerosis.", "journal": "Arteriosclerosis, thrombosis, and vascular biology", "year": "2026", "abstract": "Smooth muscle cell (SMC) derived cells form the bulk of cells in atherosclerotic lesions and modulate lesion stability and cardiovascular disease outcomes. Unfolded protein response (UPR) markers, thin fibrous caps, and inflammation correlate with human lesion instability and rupture. In mice, UPR drives macrophage and endothelial apoptosis and inflammation, but its impact on lesion stability through SMC modulation is debated. The UPR protein Perk (protein kinase RNA-like ER kinase) was recently shown to drive SMC modulation in vivo, suggesting that depletion of SMC Perk may regulate lesion stability. SMC Perk was deleted from SMC-lineage-traced adult Ldlr-/- hypercholesterolemic mice. Lesions were scored for features of lesion stability and analyzed for differential expression at the single-cell level. Perk knockdown in primary murine SMCs was used to study Perk's effect on SMC modulation in vitro. UPR marker expression in human carotid lesions was assessed for UPR markers through scRNA-seq, bulk RNA-seq, and Xenium spatial transcriptomics. SMC Perk deletion in adult atherogenic mice did not affect weight gain or serum cholesterol levels. Lesions from Perk knockout mice resembled Perk WT counterparts with similar progression, lesion stability features, and cell populations. Scoring of UPR activity and differential expression analysis found little UPR activity in SMC and smooth muscle-derived cell populations. Perk was not required for in vitro SMC modulation in atherogenic conditions. No correlation was found between UPR markers and lesion stability or symptomatic clinical presentation in human carotid lesions, and UPR markers were expressed primarily in infiltrating leukocytes rather than in SMCs and stromal cells. SMC Perk UPR does not play a significant role in atherosclerotic SMC modulation, disease progression, or features of lesion stability in mice. Similarly, expression of markers of the Perk UPR pathway in humans does not correlate with human carotid lesion stability or clinical presentation."}]}, "alphafold": {"status": "ok", "uniprot": "P01130", "entry_id": "AF-P01130-F1", "uniprot_start": 1, "uniprot_end": 860, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P01130-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P01130-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P01130-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 777301, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P01130-F1.cif", "pdb_bytes": 548126, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P01130-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "LDLR"}}
{"gene": "PCSK9", "focus": "lipid_metabolism", "uniprot": {"gene": "PCSK9", "status": "ok", "accession": "Q8NBP7", "entry": "PCSK9_HUMAN", "protein_name": "Proprotein convertase subtilisin/kexin type 9", "function": "Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments (PubMed:18039658). Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation (PubMed:17461796, PubMed:18197702, PubMed:18799458, PubMed:22074827). Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway (PubMed:18660751). Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways", "disease": ""}, "pubmed": {"gene": "PCSK9", "status": "ok", "articles": [{"pmid": "42281165", "title": "Evaluation of DeepSeek-Generated Biochemistry Clinical Cases for Teaching Purpose.", "journal": "Biochemistry and molecular biology education : a bimonthly publication of the International Union of Biochemistry and Molecular Biology", "year": "2026", "abstract": "To overcome limitations in traditional case-based teaching, this study developed an AI-driven workflow using DeepSeek to generate contemporary, interdisciplinary clinical biochemistry cases. Through human-AI collaboration, eight structured cases covering key topics such as carbohydrate and lipid metabolism were created, each including a clinical description, molecular mechanisms, and Q&A, followed by instructor review. Fifteen medical students and 15 instructors evaluated the cases using a 5-point Likert scale across multiple dimensions, while student performance was compared between a group using AI-generated cases and a control group. The AI generated each case in 10-15\u2009min, significantly faster than manual development. Cases presented a logical progression from molecular mechanism to clinical management and incorporated recent advances such as CRISPR and PCSK9 inhibitors. Content integration received the highest ratings, though instructors scored pedagogical applicability lower. Error analysis indicated that AI excelled in maintaining logical consistency, whereas human reviewers enhanced precision in clinical details. Students who used the AI-generated cases achieved significantly higher examination scores than the control group (p\u2009<\u20090.05). In conclusion, DeepSeek-generated cases are efficient, interdisciplinary, and innovative. Human review remains essential for ensuring clinical rigor, particularly in nuanced scenarios. This collaborative approach enhances both the efficiency of case development and the educational quality of biochemistry teaching materials."}, {"pmid": "42269711", "title": "Targeting PCSK9 in Vascular Smooth Muscle Cells: An Effective Strategy to Suppress Ferroptosis and Attenuate Abdominal Aortic Aneurysm Progression.", "journal": "Cell proliferation", "year": "2026", "abstract": "Abdominal aortic aneurysm (AAA) lacks effective pharmacotherapy. This study examines whether proprotein convertase subtilisin/kexin type 9 (PCSK9) drives ferroptosis in vascular smooth muscle cells (VSMCs) and whether its pharmacological degradation mitigates disease progression. PCSK9 is enriched in VSMCs of human AAA and in murine models induced by PPE or Ang II. SMC-specific PCSK9 overexpression (PCSK9SMC OE) increases aortic diameter, aggravates elastin fragmentation and collagen deposition and elevates MMP2/9 expression. Within aortic lesions, PCSK9SMC OE enhances iron accumulation and lipid peroxidation while reducing glutathione GPX4, consistent with ferroptosis. In primary VSMCs, PCSK9 overexpression suppresses GPX4 and glutathione, increases malondialdehyde and Fe2+ levels and impairs viability, whereas PCSK9 knockdown attenuates Ang II-induced ferroptosis. Mechanistically, PCSK9 triggers ferritinophagy, as shown by decreased ferritin heavy chain-1 (FTH1) and nuclear receptor coactivator-4 (NCOA4), an increased LC3-II/I ratio and enhanced FTH1-LAMP1 colocalisation. Autophagy inhibition with bafilomycin A1 blocks Fe2+ accumulation and rescues ferroptotic indices. The cell-permeable peptide Cadd4 promotes PCSK9 degradation, restores FTH1 and NCOA4 and suppresses ferroptosis in VSMCs. In PPE and Ang II models, Cadd4 reduces aortic dilation, preserves medial structure and normalises ferroptosis and ferritinophagy markers. PCSK9 drives ferritinophagy-dependent ferroptosis in VSMCs, and Cadd4 represents a promising therapeutic strategy for AAA."}, {"pmid": "42269417", "title": "Context-dependent regulation of endothelial inflammation and atherosclerosis by endothelial microRNA-33.", "journal": "Atherosclerosis", "year": "2026", "abstract": "Atherosclerosis arises through the metabolic and inflammatory perturbation of numerous cells, including immune cells and endothelial cells (ECs). microRNA-33 (miR-33) regulates lipid metabolism and inflammatory responses of immune cells, but the impact of miR-33 on atherosclerosis progression has mixed effects, pointing to context- and cell-type-specific functions. Notably, the role of EC miR-33 in atherosclerosis remains unexplored, despite the central involvement of metabolic and inflammatory pathways in EC function. We sought to determine the definitive role of EC miR-33 in atherosclerosis progression. We generated mice with an inducible EC-specific miR-33 knockout (iECKO), followed by PCSK9-AAV8 injection and western diet feeding. Detailed plaque analyses and scRNAseq were performed. For acute inflammation, we analyzed TNF\u03b1-mediated leukocyte recruitment in the air pouch model. In vitro approaches included the culture of human aortic ECs to analyze gene expression under inflammatory and lipid-laden conditions with miR-33 mimicry. iECKO mice showed accelerated lesion initiation, but this effect did not persist in advanced atherosclerosis, which is likely due to chronic hypercholesterolemia-driven downregulation of miR-33 that masks its deletion at later stages. Transcriptomic analyses revealed that cholesterol loading alters EC responses to inflammation, which can be partially rescued by miR-33 mimicry. Accordingly, iECKO mice exhibited heightened sensitivity to acute, normocholesterolemic inflammation, which is paralleled with regulation of E-selectin levels. Our work underscores the nuanced effects of miR-33 manipulation and highlights how well-described regulators of atherosclerosis progression may have unique cell type- and disease stage-dependent roles. Additionally, our work further implicates miR-33 as a regulator of EC function and identifies a new potential role in acute inflammation via E-selectin regulation."}, {"pmid": "42263662", "title": "Cholesterol metabolism in immune cells: From mechanisms to therapeutic opportunities.", "journal": "Immunity", "year": "2026", "abstract": "All immune cells engage in cholesterol metabolism, which generates a spectrum of bioactive metabolites that mainly include cholesterol itself, its biosynthetic intermediates, and oxidized or sulfated derivatives. These metabolites regulate not only cellular metabolism but also immune signaling. In addition, several functional proteins within cholesterol metabolic pathways exert non-canonical signaling functions that shape immune cell responses. Distinct immune cell types adopt specialized cholesterol metabolic programs tailored to their functional demands, and these programs are further influenced by physiological factors such as diet and aging. In human disease, immune cell cholesterol metabolism is frequently dysregulated, which highlights metabolic intervention as a promising therapeutic strategy. Accordingly, the repurposing of established metabolic drugs such as statins and PCSK9 inhibitors is gaining momentum, alongside the identification of additional therapeutic targets. A deeper understanding of how cholesterol metabolism governs immune responses will advance fundamental immunology and accelerate the development of next-generation immunotherapies."}, {"pmid": "42249453", "title": "PROTAC-mediated PCSK9 degradation attenuates atherosclerosis and improves plaque composition via suppression of NF-\u03baB/TNF-\u03b1 pathway.", "journal": "BMC medicine", "year": "2026", "abstract": "Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a critical therapeutic target for managing hyperlipidemia and atherosclerosis. We developed Cadd4, a synthetic proteolysis-targeting chimera (PROTAC) engineered to selectively induce proteasomal degradation of the PCSK9 protein. In this study, we investigate Cadd4's anti-atherosclerotic properties and concurrently evaluate the feasibility and safety of its long-term therapeutic administration. Cadd4-mediated PCSK9 degradation was assessed in mouse monocyte-macrophage leukemia cells(RAW264.7), mouse aortic vascular smooth muscle cells (MOVAS) and human umbilical vein endothelial cells (HUVECs) using immunofluorescence. Its anti-inflammatory effects were examined in lipopolysaccharide (LPS)-stimulated cells via quantitative real\u2011time PCR (qRT-PCR) and western blot. In vivo efficacy was assessed in apolipoprotein E-deficient (ApoE-/-) mice maintained on a high-fat diet (HFD). Animals received intraperitoneal injections of Cadd4 (20\u2009mg/kg every two days) or subcutaneous injections of alirocumab (3\u2009mg/kg weekly) for 12 consecutive weeks. Cadd4 induced dose-dependent PCSK9 degradation in all three cell types tested and significantly attenuated LPS-induced inflammatory responses. Notably, a 2-week intraperitoneal administration of Cadd4 led to a marked reduction in PCSK9 expression in both the liver and aorta of treated mice. In HFD-fed ApoE-/- mice, 12-week administration of Cadd4 significantly decreased atherosclerotic plaque area, enhanced collagen deposition within plaques and suppressed intra-plaque inflammation. Importantly, compared with alirocumab, Cadd4 demonstrated superior efficacy in suppressing matrix metalloproteinase (MMP) expression and increasing collagen content, effects that are likely mediated via inhibition of the NF-\u03baB/TNF-\u03b1 signaling pathway. Of note, Cadd4 mediated PCSK9 modulation did not alter plasma lipid profiles in this model. Collectively, these anti-atherosclerotic effects underscore the lipid-independent anti-inflammatory activity and plaque composition-improving capacity of Cadd4. Cadd4 potently induces PCSK9 degradation in arterial tissues, mitigates atherosclerotic progression and improves plaque composition via lipid-independent inhibition of the NF-\u03baB/TNF-\u03b1 pathway. These findings underscore the therapeutic promise of Cadd4 as a candidate for managing atherosclerotic cardiovascular disease."}]}, "alphafold": {"status": "ok", "uniprot": "Q8NBP7", "entry_id": "AF-Q8NBP7-F1", "uniprot_start": 1, "uniprot_end": 692, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-Q8NBP7-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-Q8NBP7-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-Q8NBP7-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 612206, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-Q8NBP7-F1.cif", "pdb_bytes": 430190, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-Q8NBP7-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "PCSK9"}}
{"gene": "APOB", "focus": "lipid_metabolism", "uniprot": {"gene": "APOB", "status": "ok", "accession": "P04114", "entry": "APOB_HUMAN", "protein_name": "Apolipoprotein B-100", "function": "Apolipoprotein B is a major protein constituent of chylomicrons (apo B-48), LDL (apo B-100) and VLDL (apo B-100). Apo B-100 functions as a recognition signal for the cellular binding and internalization of LDL particles by the apoB/E receptor", "disease": ""}, "pubmed": {"gene": "APOB", "status": "ok", "articles": [{"pmid": "42241510", "title": "Century of Progress on the Structure of APOB-100 in Atherogenic Lipoproteins.", "journal": "Circulation research", "year": "2026", "abstract": "APOB-100 (apolipoprotein B100) is the obligate structural protein of very low-density lipoprotein (VLDL), intermediate density lipoprotein, and low-density lipoprotein (LDL), with each atherogenic particle containing a single copy. Because circulating APOB concentration reflects particle number, it has emerged as a clinically important marker that may outperform LDL cholesterol in cardiovascular risk prediction. Historically, the large size, lipid dependence, and conformational diversity of APOB have hindered a detailed structural understanding. However, recent advances in cryo-electron microscopy and integrative modeling have transformed this landscape, yielding near-atomic models of APOB organization on human LDL and defining the structural basis for receptor recognition. This review traces the evolution of APOB structural concepts from its discovery as the main LDL scaffold to contemporary cryo-electron microscopy-derived architectures. The new structures reveal an extended scaffold that encircles the particle, accommodates large changes in lipid cargo, and presents multiple interaction surfaces for the LDL receptor. The new models reconcile decades of mutagenesis, antibody mapping, and cross-linking data and provide a mechanistic framework for understanding familial hypercholesterolemia variants, receptor binding stoichiometry, and the structural transitions that occur during VLDL to LDL remodeling. Despite these advances, intrinsic heterogeneity in particle size, lipid composition, and protein conformation imposes fundamental limits on achievable resolution, and we argue that APOB should be viewed as a dynamic structural ensemble rather than a single static molecule. Future work will require integration of structural models with targeted biochemical studies to define cooperative receptor binding mechanisms, structural determinants of remnant clearance, and the basis for association with exchangeable apolipoproteins and lipolysis regulators. Extending cryo electron microscopy to LDL subpopulations like lipoprotein(a) and VLDL remnants promises to establish new frameworks for linking APOB architecture to lipoprotein metabolism and cardiovascular disease."}, {"pmid": "42241507", "title": "Antibody E06 and the Role of Oxidized Phospholipids in Atherogenesis and Inflammation.", "journal": "Circulation research", "year": "2026", "abstract": "Oxidized phospholipids (OxPL) are generated at sites of oxidative stress and tissue injury, where they function as prototypic danger-associated molecular patterns that trigger inflammation, cell death, and tissue remodeling. The natural IgM antibody E06, and derivative formats such as E06-scFv, recognize the phosphocholine epitope on OxPL but not on native phospholipids, providing powerful tools to probe the biology of OxPL across cardiovascular and noncardiovascular disease. In this review, we summarize experimental and translational evidence implicating OxPL as mediators of atherogenesis, myocardial ischemia-reperfusion injury, nonalcoholic steatohepatitis and hepatocellular carcinoma, bone loss, lung fibrosis and acute lung injury, sepsis, neuroinflammation, and pain. In multiple murine models, genetic or passive approaches that express or deliver E06-based constructs neutralize OxPL, attenuate inflammation, improve tissue function, and reduce lesion burden, establishing OxPL as an actionable driver rather than a passive byproduct of oxidative stress. We further highlight how E06 has been leveraged to develop sensitive immunoassays for OxPL on apoB-containing lipoproteins and on Lp(a) (lipoprotein[a]; OxPL-apo[a]). These biomarkers consistently associate with incident and recurrent cardiovascular events and link OxPL biology to human lipoprotein metabolism, particularly the preferential enrichment of OxPL on Lp(a). We review emerging data on how established and novel therapies, including statins, PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, lipoprotein apheresis, and Lp(a)-targeted antisense and RNA-based agents, modulate OxPL, and discuss how these interventions may help test the OxPL hypothesis in outcomes trials. Finally, we outline key challenges and opportunities for translating OxPL-directed strategies to the clinic, including issues of specificity, immunogenicity, timing, and patient selection. Collectively, these insights position OxPL and its selective neutralization by E06-like antibodies as a unifying mechanism and promising therapeutic target across diverse inflammatory and cardiometabolic diseases."}, {"pmid": "42172871", "title": "Peptide-mediated delivery of an \u03b1-synuclein-targeting antisense oligonucleotide: Pharmacokinetics, safety, and central nervous system efficacy in a synucleinopathy model.", "journal": "Drug metabolism and disposition: the biological fate of chemicals", "year": "2026", "abstract": "Effective blood-brain barrier penetration is a major challenge for antisense oligonucleotide (ASO) therapies targeting neurodegenerative diseases. We utilized an 11-amino acid peptide derived from apolipoprotein B (ApoB11) that binds the low-density lipoprotein receptor to cross the blood-brain barrier, to deliver an ASO systemically to the central nervous system (CNS) and suppress targeted transcripts in neurodegenerative disease models. This study evaluates the pharmacokinetics, CNS penetration, and therapeutic efficacy of ApoB11:2'-O-methyl ASO-\u03b1-Syn, an ASO for \u03b1-synuclein (\u03b1-Syn) suppression in synucleinopathies. After a single intraperitoneal injection (2 mg/kg) in C57BL/6 mice, ApoB11:ASO-\u03b1-Syn showed robust brain penetration, reaching peak concentrations (maximum concentration [Cmax] = 0.14 nmol/mg) at 1.5 hours and persisting at high levels over the 96-hour observation period, indicating prolonged CNS retention. Immunofluorescence confirmed widespread uptake in neurons and endothelial cells. The ASO also accumulated in the liver (Cmax = 419.5 nmol/mg, t1/2 = 104.9 hours), consistent with receptor-mediated uptake. Acute and subacute toxicity studies revealed no systemic toxicity at the highest nonlethal dose (32 mg/kg). In a mouse model of dementia with Lewy bodies overexpressing human \u03b1-Syn, ApoB11:ASO-\u03b1-Syn reduced \u03b1-Syn mRNA and protein levels in the hippocampus and cortex by \u223c50% at 16 mg/kg, a reduction that is biologically meaningful based on human genetic evidence (SNCA duplications/triplications) and preclinical studies. These results demonstrate that ApoB11 is an effective ASO carrier for CNS delivery, and that partial \u03b1-Syn reduction is expected to have disease-relevant effects, supporting its potential as a therapeutic strategy for synucleinopathies. SIGNIFICANCE STATEMENT: This study demonstrates that systemically delivered ApoB11-conjugated antisense oligonucleotides effectively cross the blood-brain barrier, achieve sustained central nervous system retention, and produce a biologically meaningful reduction (\u223c50%) in \u03b1-synuclein expression in a transgenic mouse model of synucleinopathy. These findings highlight a minimally invasive, peptide-mediated strategy for targeting neurodegenerative diseases and overcoming major delivery limitations of antisense oligonucleotide therapies."}, {"pmid": "42061645", "title": "Triazine Thiols Decrease Apolipoprotein B Secretion From Hepatocytes Through Inhibition of Human Carboxylesterase 1.", "journal": "Cellular and molecular gastroenterology and hepatology", "year": "2026", "abstract": "Homozygous familial hypercholesterolemia is an autosomal genetic disorder that generates increased levels of low-density lipoproteins in the serum. Elevated low-density lipoprotein results in hypercholesterolemia leading to potentially fatal cardiovascular disease. Patients with homozygous familial hypercholesterolemia are often refractory to standard cholesterol-lowering treatments. Some available pharmaceuticals developed specifically for homozygous familial hypercholesterolemia can elevate hepatic lipid levels and in other cases have limited accessibility. Previously, we identified a family of triazine thiol compounds that effectively reduce apolipoprotein B-100 secretion by hepatocytes. In mice with humanized livers, triazine thiols effectively lowered serum cholesterol, triglycerides, low-density lipoproteins and lipoprotein(a). Despite their effectiveness, the mode of action of triazine thiols was unknown. Affinity-based mass spectrometry, biochemical assays, molecular modeling, and gene-edited induced pluripotent stem cell-derived hepatocyte-like cells were used to identify and characterize the molecular target and mechanism of action of triazine thiols. Using affinity-based mass spectrometry, we identified Carboxylesterase 1 (CES1) as a triazine thiol binding protein. Biochemical assays demonstrated that triazine thiols are slow-binding, allosteric, covalent CES1-specific inhibitors. Molecular modeling identified a predicted binding site within CES1 near cysteine 390, and loss of this cysteine conferred resistance to triazine thiol-mediated inhibition. Moreover, hepatocyte-like cells derived from CES1-/- induced human pluripotent stem cells exhibited a significant reduction in APOB secretion, mimicking the effect of triazine thiol treatment. This study establishes triazine thiols as novel, highly specific carboxylesterase 1 inhibitors, providing insight into their mechanism and highlighting carboxylesterase 1 inhibition as an approach for treating hypercholesterolemia."}, {"pmid": "42052822", "title": "ApoA-I Dissociated From Human HDL Retains its Acceptor Properties in ABCA1-mediated Cholesterol Efflux From RAW 264.7 Macrophages in Coronary Artery Disease.", "journal": "Frontiers in bioscience (Landmark edition)", "year": "2026", "abstract": "The significance of cholesterol efflux as a predictor of coronary artery disease (CAD) remains controversial. The intracellular cholesterol export via the ABCA1 transporter involves the acceptance of cholesterol by both lipid-free apolipoprotein A-I and high-density lipoproteins (HDL). An estimate of the efficiencies of two reactions is thus required. HDL from the plasma of 63 control and 76 male CAD patients was obtained by the precipitation of apoB-containing lipoproteins and denatured by urea. We measured apoA-I dissociation concomitant with HDL denaturation by agarose gel electrophoresis followed by immunodetection and the expression of 65 preselected genes in blood mononuclear cells by real-time PCR. The total cholesterol efflux capacity (CEC) of ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux from RAW 264.7 macrophages, when pre\u03b2-HDL and \u03b1-HDL act as competitive inhibitors of each other for the binding to ABCA1 transporter, was measured with intact HDL and pre-denatured HDL as a source of lipid-free apoA-I. The phospholipid:apoA-I and cholesterol:apoA-I ratios in HDL from CAD patients were higher than those for control patients across the full range of plasma HDL-cholesterol levels. ApoA-I partitioned 1.5-fold higher into the water phase for HDL from CAD patients relative to controls. In CAD patients, the dissociation parameter D was inversely correlated with absolute and normalized per apoA-I phospholipid and cholesterol levels in HDL. For control patients, the D parameter was positively correlated with ABCA1 gene expression. For CAD patients, the D parameter was positively correlated with PLTP and inversely with CUBN and ALB gene expression. ApoA-I functionality in ABCA1-mediated cholesterol efflux from RAW 264.7 macrophages to lipid-free apoA-I generated from urea-induced HDL denaturation was similar for HDL from control and CAD groups. The retained CEC of lipid-free apoA-I in CAD may be masked by competition with \u03b1-HDL, which has a lower CEC, for ABCA1 binding to pre\u03b2-HDL. The enrichment of HDL with cholesterol and phospholipids may contribute to the increased apoA-I dissociation from HDL in CAD. Estimates of both lipid-free apoA-I and intact HDL may be a prerequisites for a detailed study of ABCA1-mediated cholesterol efflux, which could allow these apoA-I forms to be identified as CAD predictors."}]}, "alphafold": {"gene": "APOB", "uniprot": "P04114", "status": "error", "error": "<HTTPError 404: 'Not Found'>"}}
{"gene": "CFTR", "focus": "cystic_fibrosis", "uniprot": {"gene": "CFTR", "status": "ok", "accession": "P13569", "entry": "CFTR_HUMAN", "protein_name": "Cystic fibrosis transmembrane conductance regulator", "function": "Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis (PubMed:26823428). Mediates the transport of chloride ions across the cell membrane (PubMed:10792060, PubMed:11524016, PubMed:11707463, PubMed:12519745, PubMed:12529365, PubMed:12588899, PubMed:12727866, PubMed:15010471, PubMed:17036051, PubMed:1712898, PubMed:17182731, PubMed:19398555, PubMed:19621064, PubMed:22178883, PubMed:25330774, PubMed:26846474, PubMed:28087700, PubMed:8910473, PubMed:9804160). Possesses an intrinsic ATPase activity and utilizes ATP to gate its channel; the passive flow of anions through the channel is gated by cycles of ATP binding and hydrolysis by the ATP-binding domains (PubMed:11524016, PubMed:15284228, PubMed:26627831, PubMed:8910473). The ion channel is also permeable to HCO(3)(-); selectivity depends on the extracellular chloride concentration (PubMed:15010471, PubMed:19019741). In vitro, mediates ATP-dependent glutathione flux (PubMed:12727866). Exerts its function also by modulating the activity of other ion channels and transporters (PubMed:12403779, PubMed:22121115, PubMed:22178883, PubMed:27941075). Plays an important role in airway fluid homeostasis (PubMed:16645176, PubMed:19621064, PubMed:26823428). Contributes to the regulation of the pH and the ion content of the airway surface fluid layer and thereby plays an important role in defense against pathogens (PubMed:14668433, PubMed:16645176, PubMed:26823428). Modulates the activity of the epithelial sodium channel (ENaC) complex, in part by regulating the cell surface expression of the ENaC complex (PubMed:17182731, PubMed:17434346, PubMed:27941075). Inhibits the activity of the ENaC channel containing subunits SCNN1A, SCNN1B and SCNN1G (PubMed:17182731). Inhibits the activity of the ENaC channel containing subunits SCNN1D, SCNN1B and SCNN1G, but not of the ENaC channel containing subunits SCNN1A, SCNN1B and SCNN1G (PubMed:17182731, PubMed:27941075). May regulate bicarbonate secretion and salvage in epithelial cells by regulating the transporter SLC4A7 (PubMed:12403779). Can inhibit the chloride channel activity of ANO1 (PubMed:22178883). Plays a role in the chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation (PubMed:19923167, PubMed:27714810, PubMed:29393851)", "disease": ""}, "pubmed": {"gene": "CFTR", "status": "ok", "articles": [{"pmid": "42278883", "title": "Nasal Epithelial Organoids as Translational Platforms in Inflammatory, Infectious, and Precision Medicine Applications: A Systematic Review.", "journal": "Journal of clinical medicine", "year": "2026", "abstract": "Background/Objectives: The airway epithelium plays a central role in host defense, inflammatory signaling, and disease progression across infectious, inflammatory, and genetic respiratory disorders. Human nasal epithelial organoids have emerged as accessible and patient-specific in vitro platforms with increasing translational relevance. This systematic review aimed to critically evaluate the current evidence on nasal epithelial organoid models, focusing on donor characteristics, culture methodologies, differentiation strategies, and translational applications. Methods: A systematic search of PubMed/MEDLINE, Embase, Scopus, Ovid MEDLINE, and Cochrane Library was conducted for studies published between 1990 and April 2026. The review followed PRISMA guidelines and was structured according to the PICOTS framework. Eligible studies included in vitro experimental investigations using human-derived nasal epithelial organoids in infectious, inflammatory, or precision medicine contexts. Risk of bias was assessed using the QUIN tool. Results: Seventeen studies met the inclusion criteria. Applications clustered into three principal domains: infectious disease modeling, inflammatory and epithelial remodeling research, and cystic fibrosis precision medicine. Most studies employed expandable three-dimensional Matrigel-embedded organoids or organoid-derived air-liquid interface systems. Infection-focused studies demonstrated variant-specific viral replication dynamics and epithelial immune responses, while inflammatory models reproduced disease-associated differentiation and remodeling phenotypes. Cystic fibrosis oriented studies showed that organoid swelling and electrophysiological assays correlate with CFTR functional rescue and, in selected cases, clinical response. Methodological heterogeneity across protocols and outcome reporting precluded quantitative synthesis. Conclusions: Human nasal epithelial organoids represent versatile translational platforms bridging accessible patient-derived tissue and advanced airway disease modeling. Although variability in culture protocols and functional benchmarks limits standardization, these models hold significant promise for mechanistic investigation, therapeutic stratification, and precision medicine applications."}, {"pmid": "42274626", "title": "Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Dysfunction in Human Diseases: Molecular Mechanisms and Pathophysiological Implications.", "journal": "Cells", "year": "2026", "abstract": "Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction is increasingly recognized as a key contributor to a broad spectrum of human diseases beyond classical cystic fibrosis (CF). CFTR is a cAMP-regulated chloride and bicarbonate ion channel expressed in both epithelial and non-epithelial tissues, where it regulates ion homeostasis, mucosal hydration, and cellular signaling. Both inherited CFTR mutations and acquired dysfunction resulting from environmental or inflammatory factors can disrupt these physiological processes and drive disease progression. Current evidence linking CFTR dysregulation to respiratory diseases, such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), asthma, and HIV-associated airway disease, as well as cardiovascular, renal, neurological diseases, and cancer, is comprehensively discussed. Mechanistically, impaired CFTR function promotes oxidative stress, chronic inflammation, epithelial barrier dysfunction, altered mucociliary clearance, and dysregulation of signaling pathways, including NF-\u03baB, TGF-\u03b2, PI3K/Akt, MAPK, and Wnt/\u03b2-catenin. In the context of HIV infection and cigarette smoke exposure, CFTR suppression is mediated in part by TGF-\u03b2 signaling and miRNA-dependent mechanisms, resulting in compromised airway defense and increased susceptibility to pulmonary complications. Recent studies further demonstrate that CFTR dysregulation alters the expression of genes involved in fibrosis, inflammation, angiogenesis, and epithelial-mesenchymal transition (EMT). Notably, CFTR may act as either a tumor suppressor or a context-dependent oncogene, depending on tissue type and signaling milieu, highlighting its complex role in cancer biology. Advances in CFTR-targeted therapies, including potentiators, correctors, gene therapy, and combination approaches, have markedly improved outcomes in CF and may offer therapeutic potential for diseases associated with acquired CFTR dysfunction. We summarize the systemic consequences of CFTR dysregulation and the need for further mechanistic and translational research to clarify its role across diverse human diseases."}, {"pmid": "42243036", "title": "Vanzacaftor-Tezacaftor as an alternative therapeutic resource for the ETI-Resistant L467F-F508del Allele: Ex vivo prediction and exploratory clinical assessment.", "journal": "Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society", "year": "2026", "abstract": "The triple combination of Elexacaftor/Tezacaftor/Ivacaftor (ETI) has revolutionized cystic fibrosis (CF) treatment; however, a subset of patients with eligible genotypes remains unresponsive. We previously identified the L467F-F508del complex allele as a cause of therapeutic failure, conferring a severe processing defect that renders the CFTR protein refractory to ETI. To address this unmet need, we evaluated the efficacy of the next-generation combination comprising Vanzacaftor/Tezacaftor (Vnz/Tez). We utilized primary human nasal epithelial (HNE) cells derived from six patients carrying the L467F-F508del complex allele and a minimal function mutation and monitored the clinical response of a patient treated with Vanzacaftor/Tezacaftor/Deutivacaftor (VTD) via compassionate use. Mechanistic validation was performed in CFBE41o- cells. In patient-derived HNE models, treatment with Vnz/Tez resulted in a consistent and significant rescue of CFTR activity, overcoming the block previously observed with ETI. Of note, we report a patient treated with VTD who experienced a partial improvement in pulmonary function (FEV1 +220 mL) and exercise tolerance and a decrease of sweat Chloride concentration from 100 to 87 mmol/L. In heterologous expression systems, Vnz/Tez, but not Elx/Tez, successfully restored the processing of the L467F-F508del mutant, promoting the formation of the mature, complex-glycosylated CFTR form. Our findings demonstrate that the Vanzacaftor/Tezacaftor combination possesses superior corrective potency capable of rescuing the severe trafficking defect of the L467F-F508del complex allele. This study identifies a promising therapeutic solution for patients currently orphaned by standard-of-care modulators and highlights the utility of integrating ex vivo screening with clinical monitoring in defining precision medicine strategies."}, {"pmid": "42239244", "title": "Colonic epithelial regeneration shapes susceptibility to ", "journal": "bioRxiv : the preprint server for biology", "year": "2026", "abstract": "Clostridioides difficile infection (CDI) susceptibility and severity are strongly associated with preexisting colonic inflammation. However, chronic inflammatory conditions such as cystic fibrosis rarely progress to symptomatic CDI despite high rates of C. difficile colonization, suggesting that inflammation alone is insufficient to explain disease vulnerability. Notably, populations relatively protected from symptomatic CDI exhibit impaired regenerative capacity within the colon epithelium. Here, we used single cell RNA sequencing of human colonoid monolayers to map markers of CDI susceptibility and severity to cell populations associated with inflammation and epithelial repair. We identified an inducible microfold-like (M-like) population that is largely absent from the healthy colon but emerges during inflammation and regeneration. These cells were enriched for markers of severe CDI, C. difficile toxin interaction genes, and elevated CCL20 and CFTR expression. Spatial imaging localized CCL20-producing cells to wound-like gaps in mock and CDI-treated colonoids, identifying a repair-associated niche active independent of infection. Following exposure to C. difficile , wound-healing transcription within the M-like lineage declined while tuft-like populations expanded and upregulated genes associated with immune cell recruitment. These findings demonstrate that epithelial regeneration shapes host CDI vulnerability. Clostridioides difficile infection can lead to severe illness and death in vulnerable populations despite available treatments. Clinical signs of inflammation during active Clostridioides difficile infection are strongly associated with disease outcome, yet these responses primarily reflect tissue damage already underway, limiting opportunities to prevent progression. In contrast, conditions linked to severe disease, including inflammatory bowel disease and antibiotic exposure, are associated with colonic inflammation before infection or at the time of diagnosis, highlighting an opportunity for earlier identification of high-risk individuals. Using human colonoid single cell transcriptomics and spatial imaging, we identified a microfold-like cell population enriched for inflammatory mediators and Clostridioides difficile toxin interaction genes linked to severe disease. This population was active even in the absence of infection, suggesting that repair-associated populations within the inflamed colon may help identify susceptibility to severe CDI before clinical progression occurs."}, {"pmid": "42231945", "title": "Red blood cell deformability as a mechanobiological marker of CFTR dysfunction in cystic fibrosis.", "journal": "iScience", "year": "2026", "abstract": "Cystic fibrosis (CF) is a genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that controls salt and fluid transport across membranes. While CFTR is mainly studied in epithelial tissues, it is also detectable in red blood cells (RBCs), with a reduced expression in individuals with CF. However, the impact of this reduction on RBC deformability remains unexplored. Here, we investigated RBC deformability in CF using osmotic gradient ektacytometry. We examined 70 subjects with CF or CFTR-related disorders and compared them with 46 healthy control subjects. Our findings identify significant and reproducible alterations in RBC deformability associated with CFTR dysfunction, partially restored in subjects receiving highly effective CFTR modulators. These results support RBC deformability as a functional phenotype of CFTR dysfunction with prognostic potential, encouraging further investigations into the role of RBC membrane channels in cellular mechanics."}]}, "alphafold": {"status": "ok", "uniprot": "P13569", "entry_id": "AF-P13569-F1", "uniprot_start": 1, "uniprot_end": 1480, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P13569-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P13569-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P13569-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 1415399, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P13569-F1.cif", "pdb_bytes": 972647, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P13569-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "CFTR"}}
{"gene": "HBB", "focus": "hemoglobinopathy", "uniprot": {"gene": "HBB", "status": "ok", "accession": "P68871", "entry": "HBB_HUMAN", "protein_name": "Hemoglobin subunit beta", "function": "Involved in oxygen transport from the lung to the various peripheral tissues LVV-hemorphin-7 potentiates the activity of bradykinin, causing a decrease in blood pressure Functions as an endogenous inhibitor of enkephalin-degrading enzymes such as DPP3, and as a selective antagonist of the P2RX3 receptor which is involved in pain signaling, these properties implicate it as a regulator of pain and inflammation", "disease": ""}, "pubmed": {"gene": "HBB", "status": "ok", "articles": [{"pmid": "42267567", "title": "Gut microbiota remodeling in ", "journal": "Zoological research", "year": "2026", "abstract": "Gastrointestinal symptoms frequently accompany anemia caused by HBB mutations, such as \u03b2-thalassemia; however, the mechanisms linking disordered hemoglobin biology to intestinal dysfunction remain incompletely understood. In this study, HBB-mutant cynomolgus monkeys were generated and analyzed together with wild-type (WT) controls through integrated metabolomic and metagenomic profiling. HBB mutation was associated with a marked shift in gut microbial ecology, characterized by reduced microbial diversity and altered abundances of Lactobacillus and Bacteroides. Metabolic profiling revealed broad perturbation of amino acid, lipid, energy, and immune-related metabolic pathways, with 3-oxooctadecanoic acid (HMDB0254633) emerging as a discriminative metabolite between WT and HBB-mutant animals. Multiomics integration indicated that HBB mutation reshaped microbiota-metabolite interactions and may thereby affect host metabolism and immune responses. To examine the functional relevance of this metabolite, 3-oxooctadecanoic acid was administered to C57BL/6 mice with castor oil-induced diarrhea. High-dose treatment alleviated diarrhea severity, improved stool parameters, limited body weight loss, and partially restored gut microbial composition. These findings provide non-human primate evidence that \u03b2-thalassemia-associated HBB mutation disrupts intestinal microbiota homeostasis and metabolic output, identifying 3-oxooctadecanoic acid as a candidate biomarker and potential regulator of gastrointestinal dysfunction. This study provides a valuable framework for understanding how host genetic variation contributes to gut microbiome remodeling and gastrointestinal manifestations in \u03b2-thalassemia. \u7531 HBB\u57fa\u56e0\u7a81\u53d8\uff08\u5982\u03b2-\u5730\u4e2d\u6d77\u8d2b\u8840\uff09\u5bfc\u81f4\u8d2b\u8840\u7684\u60a3\u8005\u5e38\u51fa\u73b0\u80c3\u80a0\u9053\u75c7\u72b6\uff0c\u4f46\u5176\u5185\u5728\u673a\u5236\u5c1a\u672a\u5b8c\u5168\u9610\u660e\u3002\u8be5\u7814\u7a76\u901a\u8fc7\u57fa\u56e0\u7f16\u8f91\u6280\u672f\u6784\u5efa HBB\u7a81\u53d8\u578b\u98df\u87f9\u7334\uff0c\u7ed3\u5408\u4ee3\u8c22\u7ec4\u5b66\u4e0e\u5b8f\u57fa\u56e0\u7ec4\u5b66\u5206\u6790\uff0c\u5c06\u5176\u80a0\u9053\u83cc\u7fa4\u7279\u5f81\u4e0e\u91ce\u751f\u578b\u5bf9\u7167\u7ec4\u8fdb\u884c\u6bd4\u8f83\u3002\u7ed3\u679c\u663e\u793a\uff1a\u7a81\u53d8\u578b\u4e0e\u91ce\u751f\u578b\u7334\u7684\u4ee3\u8c22\u7269\u8c31\u5b58\u5728\u663e\u8457\u5dee\u5f02\uff0c\u5c24\u5176\u4f53\u73b0\u5728\u6c28\u57fa\u9178\u548c\u8102\u8d28\u4ee3\u8c22\u901a\u8def\uff0c\u5e76\u53d1\u73b0\u5173\u952e\u533a\u5206\u4ee3\u8c22\u7269HMDB0254633\uff1b\u5b8f\u57fa\u56e0\u7ec4\u5206\u6790\u8868\u660e\u4e24\u7ec4\u95f4\u4e73\u9178\u6746\u83cc\u5c5e\u548c\u62df\u6746\u83cc\u5c5e\u4e30\u5ea6\u5b58\u5728\u663e\u8457\u5dee\u5f02\uff0c\u4e14 HBB\u7a81\u53d8\u578b\u5fae\u751f\u7269\u591a\u6837\u6027\u8f83\u4f4e\uff1b\u8fdb\u4e00\u6b65\u529f\u80fd\u5206\u6790\u63d0\u793a\u57fa\u56e0\u7f3a\u9677\u663e\u8457\u6539\u53d8\u4e86\u6c28\u57fa\u9178\u4ee3\u8c22\u3001\u80fd\u91cf\u4ee3\u8c22\u7b49\u5173\u952e\u901a\u8def\u3002\u8fd9\u4e9b\u6574\u5408\u6027\u53d1\u73b0\u8868\u660e HBB\u7a81\u53d8\u53ef\u80fd\u901a\u8fc7\u8c03\u63a7\u80a0\u9053\u83cc\u7fa4\u4e0e\u4ee3\u8c22\u7269\u7684\u76f8\u4e92\u4f5c\u7528\uff0c\u5f71\u54cd\u5bbf\u4e3b\u4ee3\u8c22\u548c\u514d\u75ab\u5e94\u7b54\u3002\u6b64\u5916\uff0c\u6211\u4eec\u63a2\u7d22\u4e863-\u6c27\u4ee3\u5341\u516b\u70f7\u9178\u5bf9\u84d6\u9ebb\u6cb9\u8bf1\u5bfc\u8179\u6cfbC57BL/6\u5c0f\u9f20\u80a0\u9053\u83cc\u7fa4\u7684\u5f71\u54cd\uff0c\u901a\u8fc7\u8bc4\u4f30\u7a00\u4fbf\u7387\u3001\u8179\u6cfb\u6307\u6570\u548c\u4f53\u91cd\u53d8\u5316\u7b49\u6307\u6807\uff0c\u53d1\u73b0\u9ad8\u5242\u91cf\u5e72\u9884\u7ec4\uff083_AOH\uff09\u80fd\u7f13\u89e3\u8179\u6cfb\u75c7\u72b6\u5e76\u6539\u5584\u80a0\u9053\u83cc\u7fa4\u7ec4\u6210\u3002\u8be5\u7814\u7a76\u9996\u6b21\u5728\u975e\u4eba\u7075\u957f\u7c7b\u6a21\u578b\u4e2d\u8bc1\u5b9e\u03b2-\u5730\u4e2d\u6d77\u8d2b\u8840\u53ef\u901a\u8fc7\u7834\u574f\u80a0\u9053\u83cc\u7fa4\u7a33\u6001\u5f71\u54cd\u80c3\u80a0\u5065\u5eb7\uff0c\u5e76\u786e\u5b9a3-\u6c27\u4ee3\u5341\u516b\u70f7\u9178\u53ef\u4f5c\u4e3a\u91ce\u751f\u578b\u4e0e HBB\u7a81\u53d8\u578b\u7ec6\u80de\u7684\u5171\u540c\u751f\u7269\u6807\u5fd7\u7269\uff0c\u8fd9\u4e3a\u7406\u89e3\u03b2-\u5730\u4e2d\u6d77\u8d2b\u8840\u75c7\u72b6\u7684\u6f5c\u5728\u673a\u5236\u63d0\u4f9b\u4e86\u91cd\u8981\u53c2\u8003\uff0c\u540c\u65f6\u63ed\u793a\u4e86\u5bbf\u4e3b\u57fa\u56e0\u53d8\u5f02\u5bf9\u80a0\u9053\u5fae\u751f\u6001\u8c03\u63a7\u7684\u5f71\u54cd\u3002."}, {"pmid": "42247988", "title": "Comparative in silico analysis of hemoglobin subunits HBB, HbS (p.Glu7Val), and HBA: Sequence-structure insights into sickle cell anemia.", "journal": "Computational biology and chemistry", "year": "2026", "abstract": "Sickle cell anemia is caused by a single missense mutation in the human beta globin gene (HBB) that replaced glutamic acid with valine at position 7(p.Glu7Val), producing sickle hemoglobin (HbS) and promoting polymer formation under deoxygenated conditions. In the present in silico study, genomic and protein sequences of HBB (normal beta globin), HbS variant beta globin (HbS) and hemoglobin alpha globin (HBA) were retrieved from NCBI in FASTA format and analyzed comparatively. physicochemical properties were computed using ExPASY protparam, secondary structure features were predicted using PSIPRED, and three-dimensional /quaternary structural modeling was performed using SWISS-MODEL with template selection from PDB. The ProtParam analysis display that the p.Glu7Val substitution in HBBs reduced the number of acidic residues (Asp+Glu) and shifted the theoretical PI upward(HBB:6.740, HBBs:7.131) accompanied by a\u223c30\u202fDa decrease in molecular weight and a modest increase in hydrophobicity related indices (aliphatic index and GRAVY). PSIPRED predicted predominantly alpha helical globin folds for all subunits, with only minor differences between HBB and HbS. Structural inspection of the SWISS-MODEL assemblies localized Val 7 at the Beta chain N-terminus and consistent with the classical mechanism whereby this hydrophobic substitution creates a surface stick region that can engage hydrophobic patches on neighboring deoxy Hb molecules, providing structural context consistent with HbS polymerization and downstream erythrocyte sickling. Overall, this computational workflow provides a clear sequence to structure interpretation of the HbS mutation and highlights measurable physicochemical shifts associated with SCA."}, {"pmid": "42224377", "title": "The red blood cell proteome and interactome identify a Band 3-BLVRB axis regulating hypoxic metabolic adaptation.", "journal": "Blood", "year": "2026", "abstract": "Red blood cells (RBCs) are transcriptionally silent yet dynamically remodel metabolism in response to oxygen tension. Using ultra-pure human RBCs, we generated the deepest contamination-free proteome to date (3,775 proteins) and mapped the oxygen-dependent interactome. These datasets reveal an oxygen-responsive metabolon centered on the Band 3 (SLC4A1) N-terminus. We identify biliverdin reductase B (BLVRB) as a previously unrecognized Band 3 interactor that dissociates under hypoxia, coincident with increased Band 3-deoxyhemoglobin contacts. This reversible assembly functions as an oxygen-sensitive switch coordinating redox and glycolytic remodeling. Humanized mice lacking Band 3 N-terminal segments exhibit impaired oxygen-dependent regulation of BLVRB binding to band 3, impaired hypoxic activation of glycolysis, reduced 2,3-bisphosphoglycerate synthesis, and diminished exercise tolerance, demonstrating physiological relevance. Population-scale cis-pQTLs for SLC4A1 and BLVRB suggest functions beyond canonical heme catabolism. Mechanistically, biochemical analyses in vitro suggest that hemoglobin \u03b2 (HBB), Band 3, and BLVRB can undergo S-nitrosation and may participate in trans-nitrosation reactions with the glycolytic enzyme GAPDH, whose modification at C152 inhibits enzymatic activity in vitro. Collectively, these findings define a Band 3-BLVRB axis that integrates oxygen-dependent protein interactions with thiol-based redox chemistry, providing a framework for understanding how an anucleate cell achieves metabolic adaptability through reversible protein-protein interactions and post-translational modification. These findings suggest that perturbation of the Band 3-BLVRB axis may influence oxygen delivery and metabolic flexibility during hypoxic stress, with potential relevance to high-altitude adaptation, exercise physiology, and cardiopulmonary disease."}, {"pmid": "42204401", "title": "A Dual-Viral Delivery Platform Enables Efficient Site-Specific Integration of Therapeutic-Length Genes in Human Primary Stem Cells.", "journal": "Human gene therapy", "year": "2026", "abstract": "Site-specific integration of large genes in human primary stem cells remains a significant challenge in gene therapy, particularly for treating multiallelic diseases. Gene editing efficiency in primary stem cells is heavily influenced by the delivery strategy, which often faces issues with programmability, efficiency, and specificity. Here, we developed a dual-viral delivery system, targeted integration via virus-like particles and integrase-deficient lentivirus (TIVID). This system combines virus-like Cas9 edit particles for delivering Cas9/sgRNA ribonucleoprotein complexes and integrase-deficient lentiviral vectors for delivering HDR donor templates. The TIVID system achieves a knock-in efficiency of 65% \u00b1 5% in human induced pluripotent stem cells (iPSCs). In erythroid progenitor HUDEP2 cells, TIVID mediates precise integration of a 7.1 kb HBB-GFP cassette (from cut site to cut site) at the AAVS1 locus with 20% efficiency and stable expression. Crucially, we demonstrate that TIVID overcomes stringent packaging constraints to deliver an approximately 6 kb full-length HBB therapeutic cassette into primary human CD34+ hematopoietic stem and progenitor cells. This platform achieved 5-10% targeted integration efficiency and preserved robust lineage-specific differentiation capacity, demonstrating its potential for treating \u03b2-thalassemia and other multiallelic disorders. In head-to-head comparisons, TIVID outperformed lentivirus-derived nanoparticles (\u223c50% vs. <10% at AAVS1 in K562 with M3814) and plasmid-based eePASSIGE in iPSCs (\u223c20% vs. \u223c1.5%). Compared with traditional electroporation delivery, TIVID offers lower early cytotoxicity, promotes predominantly mono-allelic integration, and exhibits enhanced compatibility with primary stem cells. By decoupling nuclease and donor delivery, TIVID circumvents the payload constraints of single-vector systems and the toxicity of physical transfection, providing a robust ex vivo engineering platform for complex gene replacement therapies."}, {"pmid": "42068978", "title": "Meta-analysis across six global biobanks identifies recessive coding associations with complex traits and diseases.", "journal": "American journal of human genetics", "year": "2026", "abstract": "Rare bi-allelic variation is a major contributor to human disease risk, yet its effects are difficult to study at scale in population cohorts owing to the limited number of individuals with putatively deleterious bi-allelic genotypes and the challenges of accurately phasing low-frequency variants. Here, we present recessive, gene-based analyses of rare and low-frequency variants in up to 948,690 exome- or whole-genome-sequenced individuals across six biobanks with linked electronic health records. Through statistical phasing, we inferred putatively damaging compound-heterozygous genotypes, increasing the number of bi-allelic damaging genotypes by 19%. Restricting to predicted loss-of-function (pLoF) variants, we identified 5,563 genes harboring bi-allelic genotypes, a 19.8% increase in putative knockouts. We then considered all low-frequency variants (minor allele frequency [MAF] <5%) and performed gene-based recessive association testing using putatively damaging bi-allelic genotypes, identifying 58 significant associations (false discovery rate [FDR] \u22641% or prec\u22647.5 \u00d7 10-7) after meta-analysis and Cauchy combination of nonsynonymous annotations. Comparing recessive and additive models, we found 17 instances where recessive effects were more pronounced, including several previously unreported associations, such as HBB with heart failure (prec = 2.6 \u00d7 10-14; padd = 0.98), LECT2 with height (prec = 3.7 \u00d7 10-14; padd = 4.1 \u00d7 10-10), and ENSG00000267561 with height (prec = 2.9 \u00d7 10-9; padd = 0.37). This study demonstrates the potential of federated approaches to study the effects of rare bi-allelic variation."}]}, "alphafold": {"status": "ok", "uniprot": "P68871", "entry_id": "AF-P68871-F1", "uniprot_start": 1, "uniprot_end": 147, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P68871-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P68871-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P68871-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 143532, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P68871-F1.cif", "pdb_bytes": 96551, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P68871-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "HBB"}}
{"gene": "MYH7", "focus": "cardiomyopathy", "uniprot": {"gene": "MYH7", "status": "ok", "accession": "P12883", "entry": "MYH7_HUMAN", "protein_name": "Myosin-7", "function": "Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction. Forms regular bipolar thick filaments that, together with actin thin filaments, constitute the fundamental contractile unit of skeletal and cardiac muscle", "disease": ""}, "pubmed": {"gene": "MYH7", "status": "ok", "articles": [{"pmid": "42282692", "title": "Beta-Adrenergic Stimulation and ", "journal": "bioRxiv : the preprint server for biology", "year": "2026", "abstract": "Hypertrophic cardiomyopathy (HCM) is the most prevalent genetic heart disorder, characterized by significant phenotypic variability even among individuals with identical MYH7 mutations. This study aims to elucidate factors contributing to this variability and identify drivers of phenotype penetrance. We compared the baseline phenotypes of a highly penetrant MYH7 H251N mutation and the variably penetrant MYH7 G256E mutation and investigated the impact of adding beta-adrenergic stimulation and homozygosity on disease phenotype penetrance using cardiomyocytes from an isogenic line of human induced pluripotent stem cells (hiPSC-CMs). Isogenic hiPSCs with MYH7 H251N and MYH7 G256E mutations were generated using CRISPR/Cas9 technology and differentiated into cardiomyocytes (CMs). Single-cell RNA sequencing (scRNAseq) and functional analysis of contractile function revealed consistent HCM phenotype presentation in H251N CMs, whereas G256E CMs exhibited a subtle and more variable phenotype. Beta-adrenergic stimulation induced a distinct metabolic stress response in G256E CMs, characterized by impaired mitochondrial ATP upregulation. Increasing mutant gene dosage from hetero- to homozygosity led to consistent increase in hypertrophic and structural gene expression changes in G256E CMs at RNA and protein levels. These changes were distinct from the changes observed with stress response. Importantly, homozygous G256E CMs exhibited a hypercontractile functional and disorganized structural phenotype. Across multiple experimental conditions, we identified consistent increase in cardiomyocyte specific transcriptomic markers such as NPPB , APOE , PDLIM3 and ANKRD1 . Our study highlights the use of a variably penetrant MYH7 mutation to investigate factors that influence HCM phenotype penetrance. Specifically, we found that mutant gene dosage and beta-adrenergic stimulation induce distinct HCM disease phenotypes, providing novel insights into mechanisms that may contribute to variable disease expression in HCM. HCM is characterized by significant phenotypic variability, complicating both diagnosis and clinical management. This study explores the factors driving HCM phenotype penetrance using isogenic hiPSC-CMs with MYH7 mutations. We demonstrate that beta-adrenergic stimulation and increased mutant gene dosage significantly impact HCM disease penetrance. Beta-adrenergic stimulation triggers metabolic stress responses, while increased gene dosage leads to a hypercontractile and structurally disorganized phenotype. These findings provide insight into how specific modifiers can shape disease-associated phenotypes in HCM model systems."}, {"pmid": "42159538", "title": "Sex and Age Specific Genetic Risk Across the Dilated and Arrhythmogenic Cardiomyopathy Spectrum: Insights From the SHaRe Registry.", "journal": "Journal of the American College of Cardiology", "year": "2026", "abstract": "Dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) are progressive cardiac muscle disorders with phenotypic and genetic overlap. Although a male predominance is noted in DCM/ACM, it remains unclear whether this extends to specific genetic subtypes or reflects variation in disease stage and whether sex influences age-dependent disease onset across pediatric and adult groups. The aim of this study was to define sex-based differences in genetic architecture and age at diagnosis of DCM/ACM across pediatric and adult populations. Genetically tested adult and pediatric DCM/ACM patients and asymptomatic genotype-positive relatives enrolled in the multicenter SHaRe (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Sex distribution across 27 DCM- and ACM-associated genes was evaluated using logistic regression. Age at diagnosis was compared across sex and genes using Kaplan-Meier cumulative incidence estimates. Among 3,410 patients, a 61% male predominance was present across subgroups of genotype positive, genotype negative, and variants of uncertain significance (P = 0.008), with significant gene-specific variation. TTN truncating variants (TTNtv) were less common in females (OR: 0.42 [95% CI: 0.33-0.54]; P < 0.01), while DSP (OR: 3.3 [95% CI: 2.35-4.78]; P < 0.01) and grouped non-TTN sarcomeric variants (ACTC1, TNNT2, MYH7, TNNC1, TNNI3, and TPM1) were more common (OR: 1.68 [95% CI: 1.15-2.47]; P < 0.001) in females compared with males with DCM/ACM. Age at diagnosis was comparable between sexes, except in TTNtv carriers, among whom males exhibited earlier disease onset compared with females (median age 45 years [Q1-Q3: 33-55 years] vs 51 years [Q1-Q3: 38-60 years]; P = 0.003). Pediatric-onset (diagnosis at <18 years) cases (n = 174) also demonstrated a male predominance (60% male) but had distinct genetic characteristics, with non-TTN sarcomeric and PKP2 variants being more prevalent compared with adult-onset disease (non-TTN sarcomeric OR: 5.5 [95% CI: 3.3-8.9; P < 0.01]; PKP2 OR: 2.8 [95% CI: 1.1-5.2; P < 0.05]) and a bimodal age at onset peaking in infancy and adolescence. Gene-specific sex differences influence disease prevalence and age at onset in DCM/ACM. TTNtv are more common with earlier onset in males, whereas DSP and non-TTN sarcomeric variants predominate in females. Pediatric-onset DCM/ACM is genetically distinct and caused predominantly by non-TTN sarcomeric variants, especially during infancy. These findings support age- and sex-informed surveillance strategies and prioritize future research into the mechanisms of observed sex-based differences."}, {"pmid": "41998504", "title": "Uncovering the gene variants in a global cohort of patients with unexplained increased left ventricular wall thickness using next-generation sequencing.", "journal": "BMC cardiovascular disorders", "year": "2026", "abstract": "Genetic analysis using massive parallel sequencing is crucial for the accurate and early diagnosis of hereditary hypertrophic cardiomyopathies and their phenocopies, especially transthyretin cardiac amyloidosis (ATTR-CA) and Fabry disease (FD). This study extends the cardio next-generation sequencing (NGS) pilot study by investigating the detection rate of gene variants causing increased left ventricular wall thickness (LVWT) using an expanded 19-gene NGS panel in a larger global cohort. This study included 2068 patients with unexplained increased LVWT enrolled at cardiological clinics across 22 countries/regions between 2020 and 2022. The NGS panel comprised 19 genes associated with hypertrophic cardiomyopathy (HCM) and its phenocopies. Sequencing was performed using the Illumina NextSeq 500 and NovaSeq 6000 systems, with variant interpretation performed according to the American College of Medical Genetics and Genomics guidelines. Novel variants were analyzed using the Human Gene Mutation Database (HGMD\u00ae), Franklin, and VarSome. Among the 2068 patients, 453 patients were positive for pathogenic/likely pathogenic variants (21.9%). The diagnostic yield for HCM was 18.4%, while that of HCM phenocopies was 3.5%, including ATTR-CA (1.5%), and FD (0.9%). In patients with a positive test (HCM or HCM phenocopies), the most prevalent HCM-related variants were MYBPC3 and MYH7 (36.4% and 34.4% of all positive samples, respectively), whereas TTR (7.1%) and GLA (4.0%) were the most common phenocopy variants. Other classical phenocopies, Noonan syndrome, Danon disease, and PRKAG2, comprised another 2.0%, 0.9%, and 0.7% of the cohort, respectively. The mean ages for patients with HCM sarcomeric gene variants, HCM phenocopy variants, FD, and ATTR-CA were 45.1\u2009\u00b1\u200917.6, 50.9\u2009\u00b1\u200923.7, 51.1\u2009\u00b1\u200919.4, and 64.6\u2009\u00b1\u200919.0 years, respectively. This study demonstrates the need to include GLA and TTR in NGS panels for patients with increased unexplained LVWT. NGS effectively identifies phenocopies often missed by imaging. Using a large, diverse cohort, this study reveals the prevalence of FD and ATTR-CA in patients with unexplained increased LVWT, reinforcing the importance of NGS for early diagnosis and targeted therapy. The online version contains supplementary material available at 10.1186/s12872-026-05834-5."}, {"pmid": "41985226", "title": "Generation of two induced pluripotent stem cell lines from female patients harboring MYH7 mutations with hypertrophic cardiomyopathy.", "journal": "Stem cell research", "year": "2026", "abstract": "Hypertrophic cardiomyopathy (HCM) is a cardiac disorder marked by left ventricular thickening and impaired diastolic function, often caused by truncating variants in MYH7 gene. In this work, we generated two human iPSC lines from female HCM patients, each carrying a distinct heterozygous MYH7 mutation (c.611G\u00a0>\u00a0T and c.505A\u00a0>\u00a0G). Both lines displayed a normal karyotype, typical pluripotent stem cell morphology, strong expression of key pluripotency markers, and retained the capacity to differentiate into cell types representing all three germ layers. These patient-specific female iPSC lines provide a valuable platform to explore inter-patient variability and the mechanistic diversity underlying MYH7-associated cardiomyopathies."}, {"pmid": "41979475", "title": "FGF12 Alleviates Cardiac Hypertrophy by Inhibiting Phosphorylation of CaM/CaMKII/CREB1 Axis.", "journal": "Circulation. Genomic and precision medicine", "year": "2026", "abstract": "Hypertrophic cardiomyopathy (HCM) arises from genetic mutations in sarcomere proteins, resulting in major structural abnormalities and limited treatment options. Patients with HCM had reduced expression of the FGF12 (fibroblast growth factor 12), but its precise functional role remains unclear. To explore FGF12's function and interactions, we utilized clustered regularly interspaced short palindromic repeats-Cas9 technology in cardiomyocytes derived from human induced pluripotent stem cells-induced cardiomyocytes, as well as in other cell lines and mouse models (MYH7R403Q/+, MYBPC3c790GtoA/c790GtoA, and transverse aortic constriction models). We transfected HCM or mice model with FGF12-coding sequence and FGF12-\u0394NLS plasmids or adeno-associated virus 9 vectors to reduce myocardial hypertrophy. As hypertrophy progressed, we used cleavage under targets and tagmentation) sequencing and AlphaFold3 on myocardial tissues from patients and induced pluripotent stem cells-induced cardiomyocytes. To predict mitochondrial function in cardiomyocytes, we measured mitochondrial Ca2+ concentrations and reactive oxygen species content. First, we observed a decrease in FGF12 expression and a difference in its subcellular localization in patients with HCM compared with healthy volunteers. In hypertrophic mouse models, injecting adeno-associated virus 9 reduced myocardial hypertrophy. FGF12 binds to calmodulin and inhibits its phosphorylation. This interaction also suppresses the expression and phosphorylation of downstream proteins, including CaMKII, ERK1/2, CREB1, and MCU. The nuclear-localization FGF12 binds to the promoter region of CREB1. FGF12 inhibits the expression of the CREB1-MCU axis expression, leading to reductions in both mitochondrial Ca2+ concentration and mitochondrial reactive oxygen species. This study reveals a pathological mechanism associated with HCM linked to FGF12. FGF12, located outside the nucleus, suppresses the expression of metabolism-related genes by reducing the phosphorylation levels within the calmodulin-ERK1/2-CREB1-MCU axis. In contrast, the nuclear localization of FGF12 facilitates its binding to the promoter regions of CREB1, inhibiting CREB1 expression. This dual action maintains cardiomyocyte function and mitochondrial homeostasis. Our findings position FGF12 as a promising therapeutic target for HCM."}]}, "alphafold": {"status": "ok", "uniprot": "P12883", "entry_id": "AF-P12883-F1", "uniprot_start": 1, "uniprot_end": 1935, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P12883-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P12883-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P12883-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 1855610, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P12883-F1.cif", "pdb_bytes": 1283606, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P12883-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "MYH7"}}
{"gene": "KCNQ1", "focus": "arrhythmia", "uniprot": {"gene": "KCNQ1", "status": "ok", "accession": "P51787", "entry": "KCNQ1_HUMAN", "protein_name": "Potassium voltage-gated channel subfamily KQT member 1", "function": "Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of cardiomyocyte excitability and important in normal development and functions of myocardium, inner ear, stomach and colon (PubMed:10646604, PubMed:25441029). Associates with KCNE beta subunits that modulates current kinetics (PubMed:10646604, PubMed:11101505, PubMed:19687231, PubMed:8900283, PubMed:9108097, PubMed:9312006). Induces a voltage-dependent current by rapidly activating and slowly deactivating potassium-selective outward current (PubMed:10646604, PubMed:11101505, PubMed:25441029, PubMed:8900283, PubMed:9108097, PubMed:9312006). Also promotes a delayed voltage activated potassium current showing outward rectification characteristic (By similarity). During beta-adrenergic receptor stimulation, participates in cardiac repolarization by associating with KCNE1 to form the I(Ks) cardiac potassium current that increases the amplitude and slows down the activation kinetics of outward potassium current I(Ks) (By similarity) (PubMed:10646604, PubMed:11101505, PubMed:8900283, PubMed:9108097, PubMed:9312006). Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current (PubMed:10713961). When associated with KCNE3, forms the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions (PubMed:10646604). This interaction with KCNE3 is reduced by 17beta-estradiol, resulting in the reduction of currents (By similarity). During conditions of increased substrate load, maintains the driving force for proximal tubular and intestinal sodium ions absorption, gastric acid secretion, and cAMP-induced jejunal chloride ions secretion (By similarity). Allows the provision of potassium ions to the luminal membrane of the secretory canaliculus in the resting state as well as during stimulated acid secretion (By similarity). When associated with KCNE2, forms a heterooligomer complex leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current (PubMed:11101505). When associated with KCNE4, inhibits voltage-gated potassium channel activity (PubMed:19687231). When associated with KCNE5, this complex only conducts current upon strong and continued depolarization (PubMed:12324418). Also forms a heterotetramer with KCNQ5; has a voltage-gated potassium channel activity (PubMed:24855057). Binds with phosphatidylinositol 4,5-bisphosphate (PubMed:25037568). KCNQ1-KCNE2 channel associates with Na(+)-coupled myo-inositol symporter in the apical membrane of choroid plexus epithelium and regulates the myo-inositol gradient between blood and cerebrospinal fluid with an impact on neuron excitability (By similarity) Non-functional alone but modulatory when coexpressed with the full-length isoform 1", "disease": ""}, "pubmed": {"gene": "KCNQ1", "status": "ok", "articles": [{"pmid": "42238462", "title": "Wavelet Decomposition-Based Genomic Analysis of the Human Electrocardiogram.", "journal": "medRxiv : the preprint server for health sciences", "year": "2026", "abstract": "The electrocardiogram (ECG) encodes the electrical activity of the heart across multiple timescales, yet standard clinical analysis collapses this rich signal into a handful of scalar measurements that discard most of the waveform's structure. Whether the frequency signals lost in this reduction carry heritable biological information relevant to cardiovascular disease risk remains unclear. Here we decompose resting 12-lead ECGs from 47,052 White British UK Biobank participants into 84 frequency-specific energy features using Daubechies-6 wavelet analysis across 12 leads and 7 decomposition levels, and perform independent genome-wide association analyses on each feature. We identify 67 independent loci and refine these to 101 high-confidence causal variants (posterior inclusion probability > 0.80) through Bayesian fine-mapping; associated loci converge on genes governing cardiac conduction and myocardial integrity, including SCN5A, TTN, KCNQ1, and DSP, alongside less-characterized cardiomyopathy candidates. SNP-based heritability estimates range from 0.03 to 0.26, with the strongest signals in mid-frequency bands (D6-D4, ~4-32 Hz) of Lead I and aVR, and strong inter-lead genetic correlations indicate a coordinated genetic architecture underlying the waveform. Integrating these features with FinnGen R12 cardiovascular phenotypes reveals genetic correlations reaching 0.56 with heart failure, driven predominantly by energy in the highest-frequency band (D1, 125-250 Hz), a spectral range routinely filtered from clinical ECGs and previously regarded as acquisition noise. These results reframe the electrocardiogram as a multi-frequency genetic phenotype, expand the set of cardiac loci discoverable from ECG data, and implicate high-frequency cardiac electrical activity as an underexplored dimension of cardiovascular disease risk."}, {"pmid": "42165438", "title": "Discovery of Small-Molecule Inhibitors of the KCNQ1/Kv7.1 Potassium Channel with Virtual Screening and Functional Validation in Electrophysiological Assays and KCNQ1-Knockout Neural Stem Cells.", "journal": "ACS chemical neuroscience", "year": "2026", "abstract": "Voltage-gated potassium channel KCNQ1 (Kv7.1) plays a critical role in electrical excitability in the heart, gut, and brain. Together with the auxiliary subunit KCNE1, KCNQ1 generates a slow delayed rectifier current (IKs) that is essential for cardiac repolarization. Mutations and dysregulation of this channel are found in channelopathies leading to sudden death, long-QT syndrome, atrial fibrillation, epilepsy, deafness, diabetes, and neuropsychiatric disorders. Although KCNQ1 and related potassium channels are promising therapeutic targets, there are few potent, selective, and therapeutically safe inhibitors and activators available for these proteins. A virtual screening of 36,374 compounds was conducted against KCNQ1, followed by in silico analyses that identified eight potential ligand candidates for experimental evaluation using human KCNQ1 coexpressed with KCNE1 in Xenopus laevis oocytes. Electrophysiological recordings showed that the benzodiazepine-based ligand Zinc13732787 was a potent inhibitor of the channel complex, without affecting KCNQ2/KCNQ3. Based on virtual screening and molecular docking, the 1-(3-chlorophenyl)-urea substituent on the benzodiazepine core is important for selective inhibition of KCNQ1/KCNE1, as further supported by structure-activity relationship and stereochemical exploration of Zinc13732787. Furthermore, low concentrations of Zinc13732787 reduced neurite outgrowth in human neuronal stem cells (NSCs), mirroring the phenotype observed in homozygous KCNQ1-knockout cells. Importantly, Zinc13732787 did not affect NSC proliferation, nor did it induce cytotoxicity. In homozygous KCNQ1-knockout NSCs, compound Zinc13732787 had no effect on neurite outgrowth, indicating high target specificity. These findings suggest that this compound is a valuable tool for investigating the physiological and pathological roles of KCNQ1 across various tissues. Additionally, it could be used as a precursor for novel antiarrhythmic agents as well as for epilepsy and neuropsychiatric conditions."}, {"pmid": "42133816", "title": "Machine learning-guided risk stratification for Long QT Syndrome genetic variants with hiPSC-derived cardiomyocytes.", "journal": "Cardiovascular research", "year": "2026", "abstract": "Long QT syndrome (LQTS) is a life-threatening genetic disorder characterized by prolonged QT intervals on electrocardiograms. Congenital forms are mostly associated with variants in the KCNQ1 and KCNH2 genes. Among pathogenic or likely pathogenic (P/LP) variants, some are associated with a significantly higher incidence of cardiac events compared to others. While therapies have significantly reduced mortality, some patients are unresponsive or intolerant to therapy, perpetuating their arrhythmic risk, including sudden cardiac death. Current approaches for risk stratification are insufficient, highlighting the critical need for more accurate identification and management of patients carrying high risk genetic variants.Here, we aimed to develop a refined risk stratification model for P/LP variants by applying machine learning classification to electrophysiological data measured in patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Ten patient-specific hiPSC lines, each carrying one of six pathogenic or likely pathogenic (P/LP) variants in the KCNQ1 or KCNH2 genes, along with two healthy control hiPSC lines, were differentiated into cardiomyocytes (hiPSC-CMs). Electrophysiological responses from multielectrode array recordings at baseline and after application of selective ion channel blockers or pro-arrhythmic compounds were used to train a machine learning model to classify variant-specific risk levels based on in vitro electrophysiological readouts. An independent validation cohort of two additional KCNH2 hiPSC lines was used to test the model's performance in predicting single-variant risk.Our findings revealed a correlation between variant risk level, hiPSC-CM electrophysiological profiles, and drug responses. The machine learning classifier, trained on multielectrode array recordings, achieved 89% accuracy in classification of P/LP genetic variants according to the associated risk levels. This study demonstrates that integrating hiPSC-CM electrophysiological profiling with machine learning provides a robust method for granular variant-specific risk stratification of LQTS patients."}, {"pmid": "42056480", "title": "Role of natural inter-individual variability in the different penetrance of congenital long QT syndromes (LQTS) types 1 and 2: an in silico approach.", "journal": "Scientific reports", "year": "2026", "abstract": "Congenital Long QT Syndrome types 1 and 2 (LQT1 and LQT2) are caused bymutations in the KCNQ1 and KCNH2 genes, responsible for the IKs and IKr currents, respectively. However, the penetrance of these mutations is highly variable, since some carriers remain asymptomatic, while others exhibit severe clinical manifestations. To elucidate how physiological variability in other cardiac ionic currents may influence the arrhythmic phenotype, human ventricular action potentials were simulated in silico using the O'Hara-Rudy dynamic model implemented in the Virtual Assay software. Conductances of nine key ionic currents were randomly modified within physiologically plausible ranges and the resulting population of models was validated under stress conditions. LQT1 and LQT2 cohorts were generated by reducing IKs by 80% and IKr by 60%, respectively. These cohorts were stratified into four risk categories based on action potential duration (APD) under different conditions and the occurrence of arrhythmic events. LQT1 models demonstrated impaired adaptation to adrenergic stimulation, whereas LQT2 models showed marked APD prolongation at rest. Risk stratification revealed a higher incidence of arrhythmic events in LQT2 (7.6%) compared to LQT1 (0.55%). Regression analyses identified IKr and IK1 as protective currents, while INaL and ICaL were major contributors to APD prolongation in both types. Simulated blockade of L-type Ca\u00b2\u207a channels effectively shortened APD and reduced the proportion of high-risk models. The natural variability in ionic current profiles contributes to the phenotypic expression of LQTS and support the potential use of calcium channel blockers as therapeutic alternatives in patients unresponsive to \u03b2-blockers."}, {"pmid": "41945357", "title": "Human iPSC-Based Modeling Identifies Epigenetic Regulation at the KCNQ1 Locus During Early Islet Development That Contributes to Lower \u03b2-Cell Mass.", "journal": "Diabetes", "year": "2026", "abstract": "The strongest type 2 diabetes signal in Indigenous Americans from Arizona is in intron 15 of KCNQ1. We previously identified a functional region in this intron that contained four type 2 diabetes-associated single nucleotide polymorphisms (SNPs) (rs2299620, rs2237896, rs2237897, and rs74046911) and demonstrated functionality of this fragment using Indigenous American induced pluripotent stem cell (iPSC)-derived pancreatic islets (SC-islets). In the current study, we used isogenic iPSCs with targeted edits at these four SNPs, and three additional SNPs (rs2237895, rs60808706, and rs234864), to generate SC-islets and study the effect of these variants during different developmental stages. We identify an 11% reduction in stem cell-derived \u03b2-cells (SC-\u03b2-cells) in SC-islets with the risk alleles, suggesting an effect of these variants on \u03b2-cell mass. We further show premature endocrine commitment in cells with the risk allele and lower rate of \u03b2-cell commitment during the endocrine progenitor stages, likely due to differences in H19 and INS gene expression dynamics. We also show that the differential expression may be attributable to lower CpG methylation and higher chromatin accessibility in cells with the risk alleles. In summary, the type 2 diabetes SNPs at KCNQ1 affect SC-\u03b2-cell generation, and this effect is manifested early during development, likely via an epigenomic effect on gene regulation. We previously developed an induced pluripotent stem cell-based model to study an intronic region of KCNQ1 that represents the strongest association signal with type 2 diabetes in Indigenous Americans from Arizona. The current study builds on this model by using CRISPR/Cas9-edited isogenic cells that differ only by targeted type 2 diabetes single nucleotide polymorphisms in this intronic region. The effect of KCNQ1 type 2 diabetes single nucleotide polymorphisms on pancreatic \u03b2-cell development and the probable mechanism of this effect were previously unknown. The current study shows an effect on INS and H19 gene expression dynamics specifically during the endocrine progenitor stage of pancreatic islet development likely via an epigenomic effect on gene regulation resulting in generation of lower \u03b2-like cells. Individuals carrying KCNQ1 risk alleles for type 2 diabetes will likely benefit from therapeutics that increase pancreatic \u03b2-cell mass."}]}, "alphafold": {"status": "ok", "uniprot": "P51787", "entry_id": "AF-P51787-F1", "uniprot_start": 1, "uniprot_end": 676, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P51787-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P51787-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P51787-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 612459, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P51787-F1.cif", "pdb_bytes": 435374, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P51787-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "KCNQ1"}}
{"gene": "FGFR3", "focus": "skeletal_development", "uniprot": {"gene": "FGFR3", "status": "ok", "accession": "P22607", "entry": "FGFR3_HUMAN", "protein_name": "Fibroblast growth factor receptor 3", "function": "Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Plays a role in the regulation of vitamin D metabolism. Mutations that lead to constitutive kinase activation or impair normal FGFR3 maturation, internalization and degradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A and STAT5B. Secreted isoform 3 retains its capacity to bind FGF1 and FGF2 and hence may interfere with FGF signaling", "disease": ""}, "pubmed": {"gene": "FGFR3", "status": "ok", "articles": [{"pmid": "42082487", "title": "Targeting FGFR signaling overcomes therapeutic resistance and immune evasion in oncogenic PIK3CA-driven serous-like endometrial cancer.", "journal": "Nature communications", "year": "2026", "abstract": "Serous endometrial cancer (SEC) is an aggressive subtype of endometrial cancer (EC) with poor prognosis and limited treatment options. Here, we develop a clinically relevant, immunocompetent serous-like mouse model incorporating oncogenic PIK3CA mutation, Trp53 loss, and MYC overexpression. Using this model together with human EC cell lines, patient-derived organoids (PDOs), xenografts, and patient datasets, we investigate mechanisms underlying resistance to PI3K\u03b1-targeted therapy. Single-cell profiling reveals that FGFR1/2 upregulation associates with intrinsic resistance, whereas FGFR3 characterizes acquired resistance. Dual FGFR and PI3K\u03b1 inhibition produces superior tumor control compared with either agent alone. Mechanistically, FGFR signaling promotes immune evasion by downregulating MHC-I/HLA-mediated antigen presentation and enriching M2-type tumor-associated macrophages. FGFR inhibition reverses these changes and synergizes with anti-PD-1 therapy to enhance antitumor immune responses and establish durable immune memory. Collectively, these findings identify FGFR signaling as a key driver of therapeutic resistance and immune escape in SEC and support FGFR-targeted combination strategies."}, {"pmid": "42031074", "title": "Impact of Copy Number Alterations on Human Papillomavirus (HPV)-Induced and HPV-Independent Penile Cancers.", "journal": "Laboratory investigation; a journal of technical methods and pathology", "year": "2026", "abstract": "Penile squamous cell carcinomas (SCC) develop via transforming human papillomavirus (HPV) infection or independent of HPV. The association of copy number alterations (CNA) affecting chromosome arms, amplifications or deletions of tumor suppressor/oncogenes with HPV status and somatic mutations is largely unknown. CNA in 121 penile SCC (52% HPV associated, 48% HPV independent) were assessed using shallow whole-genome sequencing and correlated with hotspot mutations in 50 cancer driver genes. CNA were common with frequent complex co-occurrences in both etiologies. Arm-level changes included gains of 3q, 8q (48% each), 1q (36%), 1p (26%), 9q (36%), and 9p (31%) and losses of 19p (48%), 8p (44%), 19q (36%), and 3p (33%). Oncogene amplifications included broad 3q alterations (43%; TP63, SOX2, and PIK3CA) and 8q alterations (40%; MYC, HEY1, and RAD21). MYC amplifications coincided with an increased fraction of genome altered indicating genomic instability (P=.00001). Homozygous deletions affected 8p (29%; WRN, NRG1), and 3p (19%, BAP1, FANCD2, VHL) and 11q22/23 (19%, ARHGEF12, BCL9L, ATM) in both etiologies. CNA affecting TP53, CDKN2A/B, CDKN1A/B, and RB1 occurred in both, HPV-induced (16%) and HPV-independent SCC (24%), while tumor suppressor gene mutations were exclusive to HPV-independent SCC. Further differences included more amplifications on 1p in HPV-induced SCC (adjusted P = .003), compared to more 8q full-arm gains (adjusted P = .00003), amplifications of oncogenes on 8q including MYC (adjusted P = .006), and homozygous deletions of 8p (adjusted P = .03) in HPV-independent SCC. EGFR amplifications dominated in HPV-independent TP53/CDKN2A wild-type SCC without dermatoses. Together with mutations in PIK3CA, HRAS, and FGFR3, CNA represent an alternate RTK/Ras/PI3K-mediated carcinogenesis pathway. Therapeutically interesting targetable CNA such as EGFR, MTAP, and ATM occurred in >50% of advanced SCC irrespective of etiology. CNA are common in penile SCC, mainly independent of HPV-status and somatic mutations and may assist in personalized treatment strategies."}, {"pmid": "41836555", "title": "Intermittent intra-articular delivery of FGF8b enhances cartilage homeostasis and attenuates osteoarthritis progression.", "journal": "Journal of orthopaedic translation", "year": "2026", "abstract": "Osteoarthritis (OA) is a chronic disease characterized by degeneration of articular cartilage, affecting over half a billion individuals globally. Current treatments such as non-steroidal anti-inflammatory drugs are effective in symptom relief, but lack the ability to modify OA progression. Fibroblast growth factor 8b (FGF8b) plays crucial roles in chondrogenesis and cartilage formation, suggesting its potential application in cartilage homeostasis maintenance. This study aims to investigate the effect of exogenous FGF8b on cartilage protection and OA progression, and explore the underlying mechanisms. Therapeutic effects of intra-articular FGF8b injections either once weekly or once every four weeks were evaluated in OA mouse models induced by destabilization of the medial meniscus (DMM) using histological analysis, X-ray imaging, micro-computed tomography (micro-CT), immunohistochemistry (IHC), and RNA sequencing of cartilage. Additionally, the therapeutic effects and underlying mechanisms of FGF8b on human cartilage and chondrocytes were further investigated using ex vivo OA models and in vitro assays. Once-weekly administration of FGF8b attenuated cartilage degradation while exacerbating osteophyte formation in a dose-dependent manner. Higher doses of FGF8b resulted in stronger cartilage-protective effects while increased osteophyte formation. Conversely, intermittent administration of FGF8b (once every four weeks) protected cartilage from degeneration without causing significant osteophyte formation. Mechanistically, FGF8b was found to help the maintenance of cartilage homeostasis by promoting anabolic metabolism and inhibiting catabolic metabolism in chondrocytes through activation of the FGFR3-PI3K-AKT signaling pathway. Exogenous FGF8b attenuates articular cartilage degeneration by increasing anabolism and inhibiting catabolism, thereby presenting therapeutic potential for OA treatment. In this study, we demonstrate that intermittent administration of FGF8b protects articular cartilage from degeneration by increasing anabolic metabolism and inhibiting catabolic metabolism in cartilage, making it a promising disease-modifying agent for OA. Moreover, the findings offer valuable insights into optimizing the exposure regimens of FGFs to achieve safer and more effective OA treatment."}, {"pmid": "41756964", "title": "Targeting FGFR signaling overcomes therapeutic resistance and immune evasion in oncogenic PIK3CA-driven serous-like endometrial cancer.", "journal": "bioRxiv : the preprint server for biology", "year": "2026", "abstract": "Serous endometrial cancer (SEC) is an aggressive subtype of endometrial cancer (EC) with poor prognosis and limited treatment options. Here, we developed a clinically relevant, immunocompetent serous-like mouse model incorporating oncogenic PIK3CA mutation, Trp53 loss, and MYC overexpression. Using this model together with human EC cell lines, patient-derived organoids (PDOs), xenografts, and patient datasets, we investigated mechanisms underlying resistance to PI3K\u03b1-targeted therapy. Single-cell profiling reveals that FGFR1/2 upregulation associates with intrinsic resistance, whereas FGFR3 characterizes acquired resistance. Dual FGFR and PI3K\u03b1 inhibition produced superior tumor control compared with either agent alone. Mechanistically, FGFR signaling promotes immune evasion by downregulating MHC-I/HLA-mediated antigen presentation and enriching M2-type tumor-associated macrophages. FGFR inhibition reversed these changes and synergized with anti-PD-1 therapy to enhance antitumor immune responses and establish durable immune memory. Collectively, these findings identify FGFR signaling as a key driver of therapeutic resistance and immune escape in SEC and support FGFR-targeted combination strategies."}, {"pmid": "41747774", "title": "Genetic evidence that FGF21 signaling reduces problematic alcohol use and alcohol-related liver disease.", "journal": "Journal of hepatology", "year": "2026", "abstract": "Fibroblast growth factor 21 (FGF21) analogs are in development for metabolic dysfunction-associated steatotic liver disease (MASLD), but their impact on problematic alcohol use (PAU), alcohol use disorder, binge drinking, and alcohol-related liver disease (ALD) is unknown. We leveraged genome-wide association study data from the UK Biobank, FinnGen, Million Veterans Program, and GenomALC for PAU, alcohol use disorder, binge drinking, weekly drinks, and ALD. Our four-tier evaluation included: (1) multivariable Mendelian randomization (MR) and mediation with circulating FGF21 levels; (2) comparative MR of MASLD and ALD targets (PNPLA3, TM6SF2, HSD17B13) using liver fat and expression instruments; (3) receptor-focused MR of \u03b2-Klotho (KLB) and FGFR1/2/3 incorporating brain-region expression; and (4) a phenome-wide MR across 1,022 traits to assess safety. Genetically higher FGF21 protein levels were associated with lower PAU (\u03b2 = -0.097, 95% CI -0.135 to -0.059, p = 6.13 \u00d7 10-7), fewer binge episodes, reduced drinking, and lower ALD risk (odds ratio [OR] = 0.79, 95% CI 0.638-0.987, p = 0.038). Multivariable MR and mediation attributed these effects entirely to behavioral pathways (reduced drinking, improved diet) and increased basal metabolic rate. In comparative MR, FGF21 - unlike PNPLA3, or HSD17B13 - reduced alcohol outcomes: a 1-SD rise in hepatic FGF21 expression reduced PAU (\u03b2 = -0.245, 95% CI -0.409 to -0.082, p = 0.003) and ALD (OR = 0.54, 95% CI 0.417-0.697, p = 2.44\u00d710-6) risk. Receptor analyses implicated hippocampal FGFR3 (OR = 0.909, 95% CI 0.876-0.943, p = 4.28 \u00d7 10-7) and basal ganglia KLB expression, supporting a liver-brain axis. Phenome-wide MR uncovered 28 Bonferroni-significant protective associations with higher FGF21 (e.g. gout). Hepatic FGF21 expression showed fewer on-target liabilities than HSD17B13 or PNPLA3. Human genetic evidence indicates that FGF21 analogs mitigate hazardous drinking and ALD via both behavioral and metabolic pathways. These findings distinguish FGF21 from other MASLD targets and highlight its potential for precision treatment of alcohol-related disorders. This study leverages human genetic evidence to validate FGF21 - a liver-derived hormone currently in clinical trials for fatty liver disease - as a dual-action therapeutic that both curbs harmful drinking behaviors and protects against alcohol-related liver injury, addressing a critical therapeutic gap with limited existing pharmacotherapies. The results are important for clinicians and researchers seeking precision medicine strategies for alcohol use disorder and liver disease, as well as for patients who currently face limited treatment options. By pinpointing FGF21's behavioral and metabolic pathways and demonstrating a favorable safety profile, our findings support the repurposing of FGF21 analogs in clinical trials of alcohol use disorder and alcohol-related liver disease and suggest that genetic stratification could optimize patient selection for t"}]}, "alphafold": {"status": "ok", "uniprot": "P22607", "entry_id": "AF-P22607-F1", "uniprot_start": 1, "uniprot_end": 806, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P22607-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P22607-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P22607-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 719724, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P22607-F1.cif", "pdb_bytes": 508193, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P22607-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "FGFR3"}}
{"gene": "BRAF", "focus": "ras_mapk_cancer", "uniprot": {"gene": "BRAF", "status": "ok", "accession": "P15056", "entry": "BRAF_HUMAN", "protein_name": "Serine/threonine-protein kinase B-raf", "function": "Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus (Probable). Phosphorylates MAP2K1, and thereby activates the MAP kinase signal transduction pathway (PubMed:21441910, PubMed:29433126). Phosphorylates PFKFB2 (PubMed:36402789). May play a role in the postsynaptic responses of hippocampal neurons (PubMed:1508179)", "disease": ""}, "pubmed": {"gene": "BRAF", "status": "ok", "articles": [{"pmid": "42271059", "title": "Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer.", "journal": "Nature", "year": "2026", "abstract": "BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all patients with colorectal cancer (CRC), and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as encorafenib are ineffective due to MAPK pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, although approved therapies, results in short survival benefits and frequent treatment resistance and relapse1-3. Here, through rational chemical library design coupled with parallel proteomic screening, we identified dHuR as a molecular glue degrader of human antigen R (HuR), an RNA-binding protein that drives tumour growth, invasion and therapy resistance. dHuR binds to the CRBN ubiquitin ligase to create a unique benzofuran-tethered composite surface to recruit HuR as a neosubstrate by engaging its \u03b2-hairpin G-loop degron, as revealed by the cryo-electron microscopy structure of the ternary complex. dHuR abrogated BRAF expression by inducing its exon 18 skipping, and demonstrated superior suppression of BRAF-mutant CRC tumours including those gaining resistance to BRAF inhibitors. Finally, we performed kinome library CRISPR screening and revealed that inactivation of EGFR or MEK enhanced dHuR cytotoxicity, thus establishing a combinatorial strategy to treat patients with refractory BRAF-mutant CRC."}, {"pmid": "42251341", "title": "Pharmacologic reprogramming of virus-tumor crosstalk enhances measles virus antitumor activity in BRAF mutant colorectal cancer models.", "journal": "Journal of experimental & clinical cancer research : CR", "year": "2026", "abstract": "Oncolytic viruses are promising cancer biotherapies but often show limited durability as single agents due to tumor-intrinsic resistance mechanisms. Because therapeutic efficacy is shaped by dynamic virus-tumor-stromal interactions, pharmacologic strategies that reprogram this interface may enhance virotherapy responses. Here, we investigate whether targeting tumor stress and survival pathways with triptolide and its prodrug Minnelide can enhance the oncolytic efficacy of measles virus in colorectal cancer. The in vitro effects of CD46 targeted (MV-GFP) and dual targeted (MV-CD46-muPA) oncolytic MV, alone and with Triptolide were assessed in human CRC cell lines. Mechanistic studies included gene expression analysis, functional proteomics, and western blotting. In vivo efficacy of MV-CD46-muPA combined with Minnelide was evaluated in HT29 and HCT116 xenografts. Biological effects were further characterized using transcriptomic profiling (RNA-seq), targeted gene expression (NanoString), and histological analysis. Triptolide enhanced MV mediated oncolysis in vitro, particularly in BRAF V600E mutant CRC cell lines, and modulated key cancer pathways including AKT, apoptosis and metabolism. In vivo, Minnelide significantly improved the efficacy of systemically administered MV-CD46-muPA in human CRC xenografts, with greater effects in BRAF mutant (HT29) models. The combination modulated cell cycle, metabolism, and survival associated genes, promoted apoptosis, and improved intratumoral viral distribution. These molecular effects resulted in reduced tumor cell proliferation (Ki67), decreased angiogenesis (CD31), and increased apoptosis (TUNEL) relative to single agents. Triptolide and Minnelide significantly enhance the oncolytic efficacy of measles virus in colorectal cancer, particularly in BRAF-mutant tumors in vivo, through reprogramming of virus-tumor-stromal interactions. This reprogramming arises from coordinated modulation of survival, metabolic, and stromal signaling pathways and is accompanied by improved intratumoral viral distribution. These findings position virus-tumor-stromal crosstalk as a central mechanistic axis of virotherapy response and provide a strong rationale for the translational and clinical development of rational virus-drug combination strategies in colorectal cancer and other malignancies."}, {"pmid": "42245718", "title": "TIL cell therapy in HIV positive patient with metastatic melanoma: case report.", "journal": "Frontiers in oncology", "year": "2026", "abstract": "Tumor-infiltrating lymphocyte (TIL) therapy is an emerging treatment for patients with metastatic melanoma whose disease has progressed on immune checkpoint inhibitors. However, individuals living with well-controlled human immunodeficiency virus (HIV) have historically been excluded from clinical trials evaluating adoptive cell therapies, leaving uncertainty regarding safety, tolerability, immune effects, and oncologic response in this population. We present the first known case of a patient with virologically suppressed HIV receiving TIL therapy for immunotherapy-refractory metastatic melanoma. A 37-year-old man with long-standing HIV on antiretroviral therapy (ART) developed rapidly progressive, BRAF-V600E mutant metastatic melanoma involving bulky axillary disease and pulmonary metastases despite anti-PD-1 therapy, combined checkpoint blockade, and BRAF/MEK-targeted therapy. His course prior to TIL therapy was notable for minimal treatment-related toxicities and intermittent detectable low-level HIV viremia. After multidisciplinary review, he underwent TIL harvest followed by lymphodepleting chemotherapy, lifileucel infusion, and high-dose interleukin-2 (IL-2). TIL therapy was tolerated with expected toxicities, including grade 1 cytokine release syndrome and IL-2-associated grade 3 hypotension requiring brief vasopressor support. At day 44, imaging demonstrated a partial response with decreased pulmonary metastases and stabilization of axillary disease. Progression of disease was observed by day 86. CD4 counts fluctuated markedly throughout treatment, though virologic suppression was ultimately restored by day 100. This case demonstrates that TIL therapy can be feasibly administered to a patient with well-controlled HIV, with manageable toxicity and early radiographic response. These findings underscore the need for prospective inclusion of people living with HIV in cellular therapy trials to better characterize safety, immune dynamics, and predictors of durable benefit."}, {"pmid": "42215124", "title": "\u03b4-Tocotrienol re-sensitizes vemurafenib-resistant melanoma cells to BRAF inhibition via modulation of AKT signaling.", "journal": "Food research international (Ottawa, Ont.)", "year": "2026", "abstract": "Melanoma is a highly aggressive skin cancer, with mortality largely driven by the development of resistance to BRAF-targeted therapies such as vemurafenib. Although several combination strategies have been explored, durable responses in resistant disease remain limited, highlighting the need for new therapeutic approaches. \u03b4-tocotrienol (\u03b4-TT), a member of the vitamin E family, has shown anticancer activity in different tumor models, but its effects in BRAF inhibitor-resistant melanoma remain poorly characterized, particularly in the context of acquired resistance and combination treatment strategies. In this study, we investigated the antitumor activity of \u03b4-TT and its ability to restore sensitivity to vemurafenib in resistant melanoma models. To this end, two human melanoma cell lines with acquired resistance (A375R and SK-MEL-28R) were treated with \u03b4-TT alone or in combination with vemurafenib. \u03b4-TT significantly reduced cell viability and clonogenic potential, inducing G1/S cell cycle arrest via downregulation of cyclin D1/D3 and upregulation of p21. It also triggered mitochondrial apoptosis, as indicated by loss of mitochondrial membrane potential, increased Bax/Bcl-2 ratio, cytochrome c release, and activation of caspase-3 and PARP cleavage. In addition, \u03b4-TT impaired migration and invasion by decreasing MMP-2 expression and secretion. These effects were associated with inhibition of AKT signaling. Notably, \u03b4-TT restored responsiveness to vemurafenib, indicating a synergistic interaction in resistant melanoma cells. Overall, these findings provide mechanistic evidence supporting a potential role for \u03b4-TT as a modulator of drug response and support further investigation of \u03b4-TT-based combination strategies to overcome therapeutic resistance in melanoma."}, {"pmid": "42206730", "title": "Implications of ADP-Ribosylation Factor-Like Protein 4C (ARL4C) in Human Neoplasia With Special Emphasis on Ameloblastoma: A Scoping Review.", "journal": "Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology", "year": "2026", "abstract": "ADP-ribosylation factor-like protein 4C (ARL4C), a member of the ARF small GTP-binding protein subfamily, has emerged from its role as an epithelial growth regulator to become a central molecule in cancer biology. This scoping review was conducted according to the PRISMA-ScR framework, systematically maps literature from PubMed, Scopus and Web of Science up to December 2024 to synthesise evidence on ARL4C's regulatory mechanisms and its implications in tumourigenesis and relevance to ameloblastoma. Originally recognised for its role in tissue morphogenesis, ARL4C is now known to drive cancer cell proliferation, migration and invasion when dysregulated. Its expression is modulated by major signalling cascades including Wnt/MAPK, PI3K/AKT and TGF-\u03b2, as well as epigenetic factors. While primarily acting as an oncogenic driver, ARL4C exhibits context-dependent roles, occasionally functioning as a tumour suppressor. In ameloblastoma, a locally aggressive odontogenic tumour, ARL4C expression correlates with invasion and bone resorption. Notably, this influence appears independent of BRAF mutation status, suggesting a unique pathological role in this setting. ARL4C stands at the intersection of fundamental cell biology and clinical oncology. It holds promise as a biomarker for prognosis and recurrence and as a potential therapeutic target. However, its dual nature highlights the complexity of cancer signalling networks. Future research involving larger patient cohorts is essential to validate ARL4C's utility in precision oncology, particularly for the management of ameloblastoma."}]}, "alphafold": {"status": "ok", "uniprot": "P15056", "entry_id": "AF-P15056-F1", "uniprot_start": 1, "uniprot_end": 766, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P15056-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P15056-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P15056-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 689736, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P15056-F1.cif", "pdb_bytes": 489563, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P15056-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "BRAF"}}
{"gene": "PTEN", "focus": "tumor_suppressor", "uniprot": {"gene": "PTEN", "status": "ok", "accession": "P60484", "entry": "PTEN_HUMAN", "protein_name": "Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN", "function": "Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins (PubMed:9187108, PubMed:9256433, PubMed:9616126). Also functions as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring of PtdIns(3,4,5)P3/phosphatidylinositol 3,4,5-trisphosphate, PtdIns(3,4)P2/phosphatidylinositol 3,4-diphosphate and PtdIns3P/phosphatidylinositol 3-phosphate with a preference for PtdIns(3,4,5)P3 (PubMed:16824732, PubMed:26504226, PubMed:9593664, PubMed:9811831). Furthermore, this enzyme can also act as a cytosolic inositol 3-phosphatase acting on Ins(1,3,4,5,6)P5/inositol 1,3,4,5,6 pentakisphosphate and possibly Ins(1,3,4,5)P4/1D-myo-inositol 1,3,4,5-tetrakisphosphate (PubMed:11418101, PubMed:15979280). Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival (PubMed:31492966, PubMed:37279284). The unphosphorylated form cooperates with MAGI2 to suppress AKT1 activation (PubMed:11707428). In motile cells, suppresses the formation of lateral pseudopods and thereby promotes cell polarization and directed movement (PubMed:22279049). Dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion formation (PubMed:22279049). Required for growth factor-induced epithelial cell migration; growth factor stimulation induces PTEN phosphorylation which changes its binding preference from the p85 regulatory subunit of the PI3K kinase complex to DLC1 and results in translocation of the PTEN-DLC1 complex to the posterior of migrating cells to promote RHOA activation (PubMed:26166433). Meanwhile, TNS3 switches binding preference from DLC1 to p85 and the TNS3-p85 complex translocates to the leading edge of migrating cells to activate RAC1 activation (PubMed:26166433). Plays a role as a key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Involved in the regulation of synaptic function in excitatory hippocampal synapses. Recruited to the postsynaptic membrane upon NMDA receptor activation, is required for the modulation of synaptic activity during plasticity. Enhancement of lipid phosphatase activity is able to drive depression of AMPA receptor-mediated synaptic responses, activity required for NMDA receptor-dependent long-term depression (LTD) (By similarity). May be a negative regulator of insulin signaling and glucose metabolism in adipose tissue. The nuclear monoubiquitinated form possesses greater apoptotic potential, whereas the cytoplasmic nonubiquitinated form induces less tumor suppressive ability (PubMed:10468583, PubMed:18716620) Functional kinase, like isoform 1 it antagonizes the PI3K-AKT/PKB signaling pathway. Plays a role in mitochondrial energetic metabolism by promoting COX activity and ATP production, via collaboration with isoform 1 in increasing protein levels of PINK1", "disease": ""}, "pubmed": {"gene": "PTEN", "status": "ok", "articles": [{"pmid": "42286561", "title": "Engineered targeted enhancement of translation in mammalian cell.", "journal": "BMC biology", "year": "2026", "abstract": "While the central dogma outlines DNA-to-protein information flow, existing gene regulators mainly target transcription. Here, we developed the \u03bbN-Guided RNA Targeting System (\u03bbGRTS), a CRISPR-independent platform enhancing mammalian mRNA translation via specific translation-guiding RNAs (tgRNAs). \u03bbGRTS integrates \u03bbN (high-affinity BoxB binder), mutated eIF4E1 (ablated non-specific 5' cap binding, retains TIC recruitment), and auxiliary factors (HuR for dsRNA stabilization, PABP and RRM2-RRM3 for mRNA closed loops). Optimized 22-nt tgRNAs (targeting 58 bp upstream of mRNA ATG in 5' UTR) and NES-tagged proteins maximized efficacy. \u03bbGRTS outperformed dCasRX (smaller\u2009~\u200950 kDa vs.\u2009~\u2009150 kDa, single tgRNA vs. crRNA-tracrRNA), boosting functional proteins (e.g., GFP). It activated P53/PTEN, suppressing GBM cell proliferation, inducing G1 arrest, and reducing invasion in vitro. In vivo, lentiviral \u03bbGRTS inhibited orthotopic GBM in nude mice, extended survival by approximately 35-40 days, with IHC confirming P53/PTEN upregulation. Mass spectrometry showed no off-target effects. Cross-species tests (human, mouse, bovine cells) validated broad applicability via conserved eIF4E1. \u03bbGRTS offers a specific, safe translation-centric tool for gene regulation and oncology research."}, {"pmid": "42277975", "title": "Generation of a stable mouse endometrial tumor-derived cell line using conditional reprogramming.", "journal": "Biological research", "year": "2026", "abstract": "Endometrial cancer (EC) is a common malignancy of the female reproductive tract worldwide. While comprehensive genomic analyses have identified multiple genetic alterations in EC, disease models remain relatively rare, limiting the ability to conduct disease studies. Establishing a hybrid in vitro and in vivo model of EC and comparing it to its in vivo counterpart could greatly advance research into EC mechanisms and treatment strategies. We established genetically engineered EC mice (Pten flox/+; Stk11 flox/flox; LTF-Cre (PSC)) and constructed a corresponding epithelial cell line from isolated uterine tumor tissues using conditional reprogramming techniques. The cell line was successfully passaged, frozen, and stored in a biobank, providing a valuable resource for future EC research. The PSC-derived cell line stably retained the mutant alleles of Pten and Stk11 during passaging, preserving the genetic profile of the original tumor. In addition, we performed various functional assays on isolated mouse cell linesand formed tumors after subcutaneous implantation of cells in immunodeficient mice and C57BL/6 mice with an intact immune system. Hematoxylin and eosin (H&E) staining and immunohistochemical staining were used to characterize the histopathology and biomarkers of the subcutaneously implanted tumors, which were highly similar to those of the parental mouse uterine tumors. The isolated mouse cell line provides a powerful platform for basic and translational EC studies, matching well with the corresponding in vivo models. The fidelity of the cell line to human-relevant genetic alterations and tumor biology makes it a valuable tool for investigating EC pathogenesis and evaluating novel therapeutic approaches."}, {"pmid": "42263837", "title": "The WYZ-1 mouse glioblastoma stem cell model: A novel preclinical tool for tumor and therapy studies.", "journal": "Cancer letters", "year": "2026", "abstract": "We established a novel syngeneic glioblastoma stem cell (GSC) line from PDGFB-driven RCAS/tv-a glioblastomas and subsequently generated a Pten-deficient derivative, WYZ-1. In vitro, WYZ-1\u202fcells exhibited robust self-renewal, high expression of GSC markers (CD133, Nestin, SOX2), and multipotent differentiation into neuronal and astrocytic lineages. In vivo, intracranial implantation in immunocompetent mice produced highly infiltrative and vascularized tumors with marked proliferation, necrosis, and white matter invasion, closely recapitulating key histopathological features of human glioblastoma. Immunohistochemical analysis confirmed the retention of oncogenic, stem-like, and mesenchymal-associated markers. Importantly, WYZ-1 tumors displayed an immune-excluded (\"cold\") tumor microenvironment characterized by dense infiltration of immunosuppressive macrophages/microglial cells within the tumor core and restricted localization of exhausted T cells to the tumor margins. Consistent with these features, WYZ-1 tumors are resistant to temozolomide and anti-PD-1 monotherapy, with only a modest survival benefit observed following CTLA-4 blockade. Collectively, these findings establish WYZ-1 as a highly aggressive, stem-like, and immunocompetent glioblastoma model that mirrors the therapeutic resistance of human disease and provides a valuable platform for investigating tumor biology and evaluating novel immunotherapeutic strategies."}, {"pmid": "42247613", "title": "Oncogenic impact of PIK3CA, KRAS, and PTEN mutations in cervical cancer among South Indian women.", "journal": "Advances in clinical and experimental medicine : official organ Wroclaw Medical University", "year": "2026", "abstract": "Cervical cancer (CC) affects millions of women worldwide. This condition is strongly associated with human papillomavirus (HPV) infection. Oncogenic alterations are known to contribute to the development and progression of CC. This study aimed to screen for variations in selected genes associated with CC, including PIK3CA, KRAS, and PTEN, and to detect high-risk HPV genotypes 16, 18, 31, 45, 52, and 58 using gene-specific polymerase chain reaction (PCR), followed by single-strand conformation polymorphism (SSCP) analysis and confirmation using bidirectional DNA sequencing. The study included 414 participants, comprising 204 cases and 210 controls. Healthy controls were disease-free individuals participating in regular health checkups. Selected gene mutations were analyzed using PCR-based assays, SSCP, and sequence analysis. HPV genotyping was also performed. All study participants were analyzed for mutations in the PIK3CA, KRAS, and PTEN genes. The analysis revealed mutation frequencies of 6.37% for KRAS, 2.45% for PTEN, and 16.66% for PIK3CA in CC cases. These findings suggest that PIK3CA and KRAS mutations are more frequent in patients with CC than PTEN mutations. HPV infection was detected in 87.10% of patients with CC, 79.24% of participants with high-grade squamous intraepithelial lesions (HSIL), and 60.34% of participants with low-grade squamous intraepithelial lesions (LSIL). This study contributes to understanding the genetic basis of CC in South India and may facilitate the development of future targeted therapies. The high prevalence of HPV underscores its etiological significance in CC. These findings contribute to a deeper understanding of the molecular mechanisms underlying CC in this population and may support the development of targeted therapeutic strategies for high-risk individuals. Future prospective studies and functional analyses are warranted to validate the clinical significance of these mutations and clarify their role in disease progression."}, {"pmid": "42227768", "title": "SARS-CoV-2 ORF3a suppresses host antiviral interferon responses by promoting STUB1-mediated PTEN proteasomal degradation.", "journal": "Journal of virology", "year": "2026", "abstract": "Human coronaviruses (HCoVs) are a group of RNA viruses characterized by high genetic variability and cross-species transmission potential. They can cause a wide spectrum of respiratory illnesses, ranging from mild upper respiratory tract infections to severe pneumonia, and acute respiratory distress syndrome. PTEN, a well-known tumor suppressor, not only plays a crucial role in tumorigenesis but also enhances antiviral immunity by regulating IRF3 phosphorylation and promoting type I interferon production. In this study, we observed that PTEN significantly inhibited the replication of various HCoVs, including SARS-CoV-2, HCoV-229E, and HCoV-OC43. However, SARS-CoV-2 infection antagonizes the antiviral function of PTEN. Mechanistically, PTEN undergoes ubiquitination at lysine 6, followed by proteasomal degradation after SARS-CoV-2 infection. Through screening, it was found that STUB1 is the key E3 ligase responsible for PTEN degradation under SARS-CoV-2 infection. Furthermore, screening of SARS-CoV-2-encoded proteins revealed that ORF3a promotes STUB1-mediated PTEN ubiquitination and degradation at K6. Previous studies have shown that Oroxin B can exert the effect of a PTEN agonist by upregulating the expression of PTEN. In this study, we demonstrated that Oroxin B significantly enhances antiviral responses in mice. In conclusion, this study reveals the molecular mechanism by which SARS-CoV-2 evades PTEN-mediated antiviral effects, providing new insights for the development of PTEN-targeted antiviral strategies. Human coronaviruses continue to threaten global health, yet how these viruses evade our natural antiviral defenses remains poorly understood. This study reveals that PTEN, a well-known tumor suppressor, also acts as a powerful antiviral molecule capable of limiting multiple human coronaviruses, including SARS-CoV-2. We further show that SARS-CoV-2 dismantles this protection by triggering PTEN degradation through the host enzyme STUB1 and the viral protein ORF3a. This discovery uncovers a previously unknown strategy used by coronaviruses to weaken innate immunity. Importantly, we identify Oroxin B as a promising compound that enhances antiviral responses in vivo. Together, our findings provide new insight into how coronaviruses disarm host defenses and highlight PTEN as a potential target for broad-spectrum antiviral therapies."}]}, "alphafold": {"status": "ok", "uniprot": "P60484", "entry_id": "AF-P60484-F1", "uniprot_start": 1, "uniprot_end": 403, "cif_url": "https://alphafold.ebi.ac.uk/files/AF-P60484-F1-model_v6.cif", "pdb_url": "https://alphafold.ebi.ac.uk/files/AF-P60484-F1-model_v6.pdb", "pae_url": "https://alphafold.ebi.ac.uk/files/AF-P60484-F1-predicted_aligned_error_v6.json", "residue_queried": null, "cif_bytes": 392672, "cif_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P60484-F1.cif", "pdb_bytes": 275804, "pdb_path": "/ddn/data/generic/bbabajan/KAUBioMED_LLM/knowledge/alphafold/structures/AF-P60484-F1.pdb", "residue_plddt": null, "residue_confidence": "not_mapped", "gene": "PTEN"}}