Diabetologia. 2026 Oct 3. doi: 10.1007/s00125-026-06884-2. Online ahead of print.

ABSTRACT

AIMS/HYPOTHESIS: Chromatin remodelling is critical for maintaining pancreatic beta cell identity and function, yet the key regulatory mechanisms remain incompletely defined. This study aimed to investigate the role of the switch/sucrose non-fermentable (SWI/SNF) complex subunit BAF60A in preserving beta cell fate and glucose homeostasis.

METHODS: Pdx1-Cre-mediated BAF60A-knockout (BaBKO) and BAF60A-overexpressing (BaBOE) mice, together with tamoxifen-inducible adult beta cell-specific Smarcd1 knockout (BaBKO^TM) and Isl1 knockout (Isl1BKO^TM) mice, were generated to evaluate the role of BAF60A in vivo. Glucose homeostasis was assessed through glucose tolerance tests, insulin tolerance tests and glucose-stimulated insulin secretion (GSIS) assays. Multiomic analyses, including RNA-seq, ATAC-seq, Cleavage Under Targets and Tagmentation (CUT&Tag) and single-cell RNA-seq, were performed to characterise chromatin accessibility and transcriptional changes. BAF60A-interacting proteins were identified with biotin identification (BioID) and GST pull-down assays. Beta cell lineage tracing was used to assess changes in cell identity. In addition, BAF60A and the dedifferentiation marker ALDH1A3 were examined in pancreatic islets from individuals with and without type 2 diabetes.

RESULTS: BaBKO mice exhibited significant glucose intolerance, impaired GSIS and pronounced loss of beta cell identity, accompanied by the acquisition of non-beta endocrine features. Inducible deletion of Smarcd1 in adult beta cells similarly impaired beta cell maturation and promoted dedifferentiation, as confirmed by lineage tracing. BAF60A deficiency reduced enhancer accessibility and downregulated beta cell identity genes. Mechanistically, BAF60A physically interacts with the transcription factor islet-1 (ISL1) to regulate transcription of target genes. Adult beta cell-specific Isl1 deletion recapitulated key features of BAF60A deficiency and abolished the beneficial effect of BAF60A overexpression on insulin secretion. Conversely, BaBOE mice exhibited improved glucose tolerance and enhanced GSIS under high-fat diet conditions. Adeno-associated virus-mediated BAF60A overexpression markedly reduced beta cell dedifferentiation in BKS-db/db mice. In human type 2 diabetes islets, BAF60A expression was significantly reduced and inversely correlated with ALDH1A3.

CONCLUSIONS/INTERPRETATION: This work establishes BAF60A-ISL1-dependent chromatin remodelling as a key mechanism that preserves beta cell identity and function under metabolic stress, providing mechanistic insight into beta cell failure in type 2 diabetes.

PMID:42829354 | DOI:10.1007/s00125-026-06884-2

Chem Biodivers. 2026 Oct;23(10):e71778. doi: 10.1002/cbdv.71778.

ABSTRACT

Pancreatic cancer has a dismal prognosis and limited therapeutic options, highlighting an urgent need for effective treatments. Sophoricoside (SOP), a natural isoflavone glycoside, has exhibited anticancer activities in multiple malignancies, including lung cancer, glioblastoma, and hepatocellular carcinoma. We combined cellular assays, network pharmacology, machine learning, and multi-omics to investigate SOP's effects. SOP-inhibited proliferation of MIA PaCa-2, SW1990, and PANC-1 cells dose-dependently. Network pharmacology revealed 85 overlapping targets enriched in MAPK, apoptosis, and PD-L1/PD-1 pathways. Machine learning and differential expression identified PTPN1 as the core target. PTPN1 was markedly upregulated in pancreatic adenocarcinoma, and its high expression correlated with poor survival and immune infiltration. Functional enrichment linked PTPN1 to TGF-β, VEGF, and metabolic reprogramming. Molecular docking suggested a possible binding mode between SOP and PTPN1, involving four predicted hydrogen bonds. SOP reduced PTPN1 mRNA, and PTPN1 knockdown phenocopied SOP's antiproliferative effect with no additivity upon combination. Collectively, this first report demonstrates that SOP restrains pancreatic cancer cell proliferation, with PTPN1 identified as a key functionally required downstream mediator based on integrative computational and functional evidence. This work offers an integrated strategy for mechanistic exploration and highlights PTPN1 as a promising therapeutic biomarker and target for pancreatic cancer.

PMID:42814531 | PMC:PMC13626263 | DOI:10.1002/cbdv.71778

Chem Biodivers. 2026 Oct;23(10):e71778. doi: 10.1002/cbdv.71778.

ABSTRACT

Pancreatic cancer has a dismal prognosis and limited therapeutic options, highlighting an urgent need for effective treatments. Sophoricoside (SOP), a natural isoflavone glycoside, has exhibited anticancer activities in multiple malignancies, including lung cancer, glioblastoma, and hepatocellular carcinoma. We combined cellular assays, network pharmacology, machine learning, and multi-omics to investigate SOP's effects. SOP-inhibited proliferation of MIA PaCa-2, SW1990, and PANC-1 cells dose-dependently. Network pharmacology revealed 85 overlapping targets enriched in MAPK, apoptosis, and PD-L1/PD-1 pathways. Machine learning and differential expression identified PTPN1 as the core target. PTPN1 was markedly upregulated in pancreatic adenocarcinoma, and its high expression correlated with poor survival and immune infiltration. Functional enrichment linked PTPN1 to TGF-β, VEGF, and metabolic reprogramming. Molecular docking suggested a possible binding mode between SOP and PTPN1, involving four predicted hydrogen bonds. SOP reduced PTPN1 mRNA, and PTPN1 knockdown phenocopied SOP's antiproliferative effect with no additivity upon combination. Collectively, this first report demonstrates that SOP restrains pancreatic cancer cell proliferation, with PTPN1 identified as a key functionally required downstream mediator based on integrative computational and functional evidence. This work offers an integrated strategy for mechanistic exploration and highlights PTPN1 as a promising therapeutic biomarker and target for pancreatic cancer.

PMID:42814531 | PMC:PMC13626263 | DOI:10.1002/cbdv.71778

Curr Mol Med. 2026 May 11. doi: 10.2174/0115665240438824260113042223. Online ahead of print.

ABSTRACT

BACKGROUND: 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/ IMP cyclohydrolase(ATIC) is a 64-kDa bifunctional enzyme, 5-aminoimidazole- 4-carboxamide ribonucleotide formyltransferase (AICART) and IMP cyclohydrolase, respectively. catalyzes the last two steps of the purine ab initio biosynthetic pathway. ATIC has been implicated in cancer progression, but its pan-cancer profile and specific prognostic utility in liver hepatocellular carcinoma (LIHC) remain incompletely defined.

METHODS: We analyzed TCGA RNA-seq data across 33 tumor types to assess ATIC expression, diagnostic performance (ROC/AUC), and prognostic associations (OS, DSS, PFI). We correlated ATIC expression with immune infiltration, TMB, MSI, and predicted neoantigen load, and constructed a LIHC-specific prognostic nomogram integrating ATIC and clinicopathologic features. Enrichment analyses (STRING, GO/KEGG, GSEA) and pharmacogenomic correlations (GDSC, CTRP) were performed to explore mechanisms and drug sensitivities.

RESULTS: ATIC was significantly upregulated in 16 tumor types, including LIHC (p<0.001). Pan-cancer ROC analyses showed high diagnostic accuracy in several cancers (examples: CHOL AUC=1.000, LIHC AUC=0.936, LUAD AUC=0.947). High ATIC expression associated with poorer OS in ACC, HNSC, LIHC, and PAAD (eg, LIHC: HR=1.39(1.04-1.85), p=0.028). In LIHC, ATIC correlated with advanced T stage, higher grade, elevated AFP, and shorter OS. Multivariable Cox regression identified ATIC expression and pathological T stage as independent predictors; time-dependent ROC for the LIHC nomogram showed AUCs of 0.711, 0.649, and 0.653 at 1, 3, and 5 years, respectively. GSEA indicated enrichment of PI3K-AKT-mTOR, MYC targets, and cell-cycle pathways in ATIC-high LIHC. High ATIC expression correlated with predicted increased sensitivity to sorafenib, doxorubicin, cisplatin, epothilone, and mitomycin in the TCGA-LIHC cohort.

DISCUSSION: ATIC upregulation across cancers links to tumor progression, immune modulation, and prognosis (LIHC), suggesting oncogenic roles in pan-cancer contexts. TCGA multi-omics show ATIC associates with immune/molecular subtypes, MSI/TMB/neoantigens, and predicts drug sensitivity, indicating diagnostic/prognostic potential.

CONCLUSION: ATIC is broadly upregulated across cancers and functions as an independent prognostic biomarker in LIHC. The ATIC-integrated nomogram shows modest predictive accuracy for LIHC survival. Our results implicate ATIC in oncogenic signaling (PI3K-AKT-mTOR, MYC, and cell-cycle) and suggest ATIC as a candidate biomarker to guide targeted and chemotherapeutic strategies in LIHC. Further in vitro and in vivo validation is warranted.

PMID:42152649 | DOI:10.2174/0115665240438824260113042223