Mol Divers. 2026 Apr 12. doi: 10.1007/s11030-026-11545-y. Online ahead of print.

NO ABSTRACT

PMID:41966666 | DOI:10.1007/s11030-026-11545-y

Metabolism. 2026 Apr 8:156607. doi: 10.1016/j.metabol.2026.156607. Online ahead of print.

ABSTRACT

Endoplasmic reticulum (ER) stress is a critical driver of pancreatic β-cell dysfunction and apoptosis. Although metformin, a drug used to treat type 2 diabetes, primarily decreases blood glucose levels by improving insulin sensitivity, its direct effects on β-cell survival remain unclear. Here, we investigated the effect of metformin on β-cell stress responses under ER stress conditions. Thapsigargin (Tg)-induced ER stress increased β-cell apoptosis in mouse islets, which was prevented by metformin in a dose-dependent manner. Treatment with metformin for 24 h suppressed the Tg-induced upregulation of unfolded protein response (UPR)-related genes, as confirmed by transcriptomic and pathway analyses. Quantitative proteomics revealed that Tg inhibited eIF2 signaling and protein translation, both of which were partially restored by metformin. Enrichment analysis further indicated the attenuation of apoptotic pathways in metformin-treated islets. Polysome profiling and puromycin incorporation assays demonstrated that metformin reduced protein translation independently of ER stress. Metformin promoted the dephosphorylation of 4E-BP1, a key initiator of cap-dependent protein translation that is activated by phosphorylation, and the antiapoptotic effect of metformin was abolished by 4E-BP1 knockdown in MIN6 cells. Phosphoproteomic analysis indicated that the activation of mTOR signaling, a kinase of 4E-BP1, in Tg-treated islets was mitigated by metformin. Taken together, these findings reveal a cytoprotective mechanism of metformin in β-cells, in which metformin suppresses ER stress-induced apoptosis through 4E-BP1-mediated inhibition of mRNA translation and modulation of mTOR signaling. This study highlights a β-cell-intrinsic action of metformin that may contribute to its long-term therapeutic benefits in diabetes management.

PMID:41962652 | DOI:10.1016/j.metabol.2026.156607

bioRxiv [Preprint]. 2026 Mar 11:2026.03.09.710586. doi: 10.64898/2026.03.09.710586.

ABSTRACT

The lack of accurate, human-based models recapitulating early-stage pancreatic ductal adenocarcinoma (PDAC) has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectory of tumor initiation and progression in vitro , validated against clinical datasets and histopathology. We demonstrate that CDKN2A loss, nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, while SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of pancreatic lineage program during PDAC initiation, alongside oncogenic AP-1-driven chromatin remodeling. Notably, we identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and the hypermethylation and silencing of essential pancreatic transcription factors. This model captures the genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a promising early intervention strategy for high-risk individuals.

PMID:41959451 | PMC:PMC13060829 | DOI:10.64898/2026.03.09.710586

bioRxiv [Preprint]. 2026 Mar 12:2026.03.10.710185. doi: 10.64898/2026.03.10.710185.

ABSTRACT

KRAS is mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), where hotspot alterations in codons 12, 13, and 61 drive tumor initiation and progression. Although distinct biochemical properties have been described for individual KRAS mutants, whether they generate unique allele-specific signaling programs in PDAC cells remains unresolved. Here, we systematically interrogated the molecular consequences of seven common KRAS mutant variants in reconstituted isogenic, KRAS-deficient PDAC cell lines by integrated transcriptomic, proteomic, and phosphoproteomic profiling. We found that baseline cellular state, rather than allele identity, was the predominant driver of molecular variation. Comparisons with established KRAS reference signatures revealed significant but moderate overlap at the mRNA level and less so at the proteome level. Pathway analyses highlighted interferon response and mitochondrial translation as recurrently altered across alleles, while phosphoproteomic data confirmed robust ERK1/2 activity and suppression of DYRK kinase substrates by mutant KRAS expression. Importantly, no robust allele-specific molecular programs were identified. Together, our study establishes a comprehensive multi-omics resource for KRAS signaling in PDAC and demonstrates that cellular context exerts a stronger influence than allele identity in shaping molecular profiles, with implications for interpreting putative allele-specific signaling dependencies and therapeutic vulnerabilities.

PMID:41959224 | PMC:PMC13060958 | DOI:10.64898/2026.03.10.710185

BioData Min. 2026 Apr 9. doi: 10.1186/s13040-026-00546-0. Online ahead of print.

NO ABSTRACT

PMID:41957754 | DOI:10.1186/s13040-026-00546-0

Hum Mutat. 2026 Apr 6;2026:8027584. doi: 10.1155/humu/8027584. eCollection 2026.

ABSTRACT

BACKGROUND: High-grade serous ovarian cancer (HGSOC) is characterized by a complex tumor microenvironment and poor prognosis, yet the roles of specific tumor-associated macrophages (TAMs) subpopulations in driving disease progression remain elusive.

METHODS: This study evaluated the prognostic relevance of FCGR2B in HGSOC. Single-cell RNA sequencing identified FCGR2B ⁺ TAMs as a distinct macrophage subpopulation with unique transcriptional features. Integrative analyses combining single-cell and bulk differentially expressed genes, macrophage-associated modules, and ferroptosis-related gene sets identified 26 candidate prognostic genes, from which a four-gene signature (CRYAB, PLAUR, EREG, and C5AR1) was derived to construct the prognostic risk model. The model was validated in an independent cohort. Immune infiltration, single-cell trajectory, copy number variation, and drug-gene associations were analyzed to explore the molecular and therapeutic implications of risk stratification.

RESULTS: HGSOC patients classified as high risk exhibited poorer survival outcomes, increased infiltration of M2-like macrophages, elevated expression of immune checkpoints, and enrichment of immune- and ferroptosis-related pathways. Trajectory and copy number variation analyses revealed stage-specific gene expression patterns and amplification-associated regulation. Drug-gene association analyses further suggested that high-risk patients may be more responsive to targeted therapies and proteasome inhibitors, whereas low-risk patients may benefit from conventional chemotherapy.

CONCLUSION: FCGR2B ⁺ TAMs are closely linked to HGSOC progression, and the proposed prognostic model based on FCGR2B ⁺ TAMs provides predictive value and potential therapeutic insights for patient stratification.

PMID:41953398 | PMC:PMC13054137 | DOI:10.1155/humu/8027584

JHEP Rep. 2026 Feb 18;8(5):101790. doi: 10.1016/j.jhepr.2026.101790. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence.

METHODS: Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry.

RESULTS: Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6⁺ ECs, enriched and spatially colocalised with tumour cells in primary tumours from patients with recurrence (p = 0.021, n = 49). A significant ANGPTL4-SDC1 ligand-receptor interaction was identified between INTS6⁺ ECs and tumour cells. Notably, INTS6⁺ ECs were enriched in microvascular invasion regions and spatially colocalised with tumour cells in patients with recurrence (p = 0.036, n = 53). These findings highlight endothelial-tumour cell interactions within the TME as potential therapeutic targets.

CONCLUSIONS: INTS6⁺ ECs are enriched in microvascular invasion regions and spatially colocalised with tumour cells in recurrent HCC, suggesting a potential role in disease recurrence and representing a promising therapeutic target within the TME.

IMPACT AND IMPLICATIONS: The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival.

PMID:41950768 | DOI:10.1016/j.jhepr.2026.101790

Ann Afr Med. 2026 Apr 8. doi: 10.4103/aam.aam_24_26. Online ahead of print.

ABSTRACT

Acute pancreatitis (AP) is an inflammatory disorder of the pancreas with clinical manifestations that range from mild, self-limited disease to severe necrotizing inflammation complicated by organ failure and significant mortality. Accurate early assessment of disease severity remains challenging, as clinical presentation at admission often does not reflect the underlying inflammatory burden or risk of progression. Biomarkers have therefore gained increasing importance as objective tools that support diagnosis, severity stratification, and prediction of complications in AP. Traditional enzymatic markers, including serum amylase and lipase, are widely used for diagnostic confirmation but show limited value in predicting outcomes. In contrast, biomarkers reflecting systemic inflammation, immune activation, and infection provide more meaningful prognostic information. These include acute-phase reactants, cytokines, and infection-associated markers such as procalcitonin. In recent years, advances in molecular and omics-based technologies have led to the identification of novel biomarkers, including pentraxin-3, microRNAs, and proteomic and metabolomic signatures, which offer earlier insight into disease progression and pathophysiological mechanisms. This review synthesizes current evidence on established and emerging biomarkers of AP, evaluates their clinical relevance and limitations, and discusses future perspectives for integrated biomarker-based approaches aimed at improving early risk assessment and individualized patient management.

PMID:41947359 | DOI:10.4103/aam.aam_24_26