Genes Dis. 2026 May 17;14(2):102243. doi: 10.1016/j.gendis.2026.102243. eCollection 2027 Feb.

NO ABSTRACT

PMID:42831172 | PMC:PMC13634571 | DOI:10.1016/j.gendis.2026.102243

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

Cell Rep Med. 2026 Oct 2:103085. doi: 10.1016/j.xcrm.2026.103085. Online ahead of print.

ABSTRACT

Hepatocellular carcinoma (HCC) management is challenging due to its complex tumor microenvironment and poor treatment responses. Here, using tumor specimens from a prospective clinical trial of combined transarterial chemoembolization (TACE) with immune checkpoint blockade (ICB), we perform exhaustive multi-omics analysis including spatial proteomics and transcriptomics, single-cell RNA sequencing, and bulk transcriptomics. These analyses reveal that treatment response is associated with enrichment of anti-tumor T cell regions that are regulated by cGAS-STING activation within immune-suppressive epithelial cells. Conversely, fibrotic processes impede these pro-response processes. Based on these insights, we test triple combination therapy consisting of cGAS activation, immune checkpoint blockade, and anti-fibrosis strategies, which shows improved efficacy over dual therapy. To identify patients who would benefit, we construct a predictive model using a group sparse learning algorithm. Our findings provide a blueprint for crafting personalized HCC therapies using next-generation biomarkers.

PMID:42826719 | DOI:10.1016/j.xcrm.2026.103085

Front Digit Health. 2026 Sep 16;8:1851723. doi: 10.3389/fdgth.2026.1851723. eCollection 2026.

ABSTRACT

Artificial intelligence (AI) is being applied across diagnostic and therapeutic workflows in hepatology. This narrative review summarizes recent advances in AI for liver disease. In medical imaging and digital pathology, computer vision enables automated quantitative analysis of ultrasound, CT, MRI, and histologic images, with the aim of improving the consistency of lesion detection, disease staging, and prognostic assessment. In biomarker research, machine learning can analyze high-dimensional liquid-biopsy and multi-omics data to develop diagnostic and prognostic models; some have outperformed conventional markers in their study cohorts. Electronic health records (EHRs) and large language models (LLMs) are also being investigated for clinical decision support and personalized management. However, most reported evidence remains retrospective, and clinical adoption is limited by data heterogeneity, poor interpretability, uncertain generalizability, and regulatory requirements. Progress will require standardized datasets, external and prospective validation, clinically relevant endpoints, and human-centered implementation before gains in model performance can be translated into better patient outcomes.

PMID:42819088 | PMC:PMC13624904 | DOI:10.3389/fdgth.2026.1851723

Biosystems. 2026 Sep 30;270:105963. doi: 10.1016/j.biosystems.2026.105963. Online ahead of print.

ABSTRACT

Biological systems can maintain their function and organization even when individual molecular components change. We propose Information Persistence Theory (IPT) to describe this idea and introduce the Meaningful Functional Organization Score (MFOS) as an estimator of coordinated biological organization. MFOS was developed using single-cell RNA-sequencing data from mouse pancreatic endocrinogenesis (GSE132188). From an initial pool of 169 candidate genes, differential-expression, functional, regulatory, protein-protein interaction, and feature-prioritization analyses were used to develop a 16-gene panel. Gene expression was scaled independently for each gene and combined with equal weights to produce a dataset-relative score ranging from 0 to 1. In the pancreatic dataset, the MFOS panel showed stronger group-associated organization than matched random gene panels, and leave-one-gene-out analysis showed that the result was not substantially dependent on any single gene. The estimator was also examined in an independent human kidney dataset (GSE131685), where the historical kidney implementation retained measurable information associated with annotated cell groups and exceeded the majority-class and label-permutation accuracy baselines. These findings indicate that MFOS can capture measurable patterns of coordinated biological organization in the datasets examined. However, MFOS is not a direct measure of information persistence, and the present datasets contain no experimental persistence labels. Longitudinal, perturbation-based, and multi-omic studies will be needed to test the proposed framework more directly.

PMID:42815614 | DOI:10.1016/j.biosystems.2026.105963

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

Cell. 2026 Sep 29:S0092-8674(26)01081-0. doi: 10.1016/j.cell.2026.09.012. Online ahead of print.

ABSTRACT

Cachexia is a major cause of morbidity in pancreatic cancer, but the cellular circuitry linking tumor progression to systemic wasting remains incompletely understood. Integrating single-cell RNA sequencing, Xenium spatial transcriptomics, multiplex immunohistochemistry, bulk transcriptomics, and functional studies across human non-cachexia, pre-cachexia, and cachexia samples, together with mouse models, we define a cachexia-associated microenvironmental niche composed of SEMA4A⁺ tumor cells, AQP9⁺ macrophages, and LOXL2⁺ cancer-associated fibroblasts. Mechanistically, SEMA4A-associated signaling promotes bone morphogenetic protein-2 (BMP2)-dependent acquisition of an AQP9-associated macrophage phenotype, and macrophage-derived CXCL8 activates LOXL2⁺ fibroblasts. LOXL2⁺ fibroblasts reciprocally enhance tumor cell FOSL1/SEMA4A signaling through exosomal N-glycosylated LOXL2. Spatial analyses demonstrate progressive enrichment of this niche with cachexia severity and association with postoperative development of cachexia in previously non-cachectic patients. These findings provide a framework linking local tumor ecosystem dynamics to cachexia progression.

PMID:42810340 | DOI:10.1016/j.cell.2026.09.012

Nat Commun. 2026 Aug 29;17(1):10311. doi: 10.1038/s41467-026-77187-8.

ABSTRACT

Type 2 diabetes (T2D) subgroups defined by clinical variables differ in disease progression and treatment response. To uncover potential molecular drivers of this heterogeneity, we performed a multi-omics analysis of 826 drug-naïve T2D patients from two phase 3 trials of the insulin sensitizer chiglitazar. Here we show that severe insulin-resistant diabetes (SIRD) is characterized by distinct miRNA profiles (e.g., miR-122-5p) correlated with liver injury, and metabolic shifts in amino acids and primary bile acids. Mild obesity-related diabetes (MOD) showed the lowest level of phenylacetylglutamine, a metabolite known to promote cardiovascular disease. Severe insulin-deficient diabetes (SIDD) exhibited high pancreas-specific miR-7-5p, while mild age-related diabetes (MARD) presented the mildest abnormalities. Finally, integrating these multi-omics signatures into machine learning models enhanced prediction of insulin sensitizer efficacy over clinical data alone. Our findings define the distinct molecular signatures of T2D subgroups, facilitating the prediction of heterogeneous treatment responses and supporting personalized clinical management.

PMID:42805981 | PMC:PMC13620142 | DOI:10.1038/s41467-026-77187-8

Adv Sci (Weinh). 2026 Sep 27:e78005. doi: 10.1002/advs.78005. Online ahead of print.

ABSTRACT

Hepatocellular carcinoma (HCC) patients show heterogeneous responses to immune checkpoint inhibitors (ICIs). This study developed ECOS-Net, a transformer-based multitask network integrating CT-derived habitat and 2.5-dimensional (2.5D) deep learning features for simultaneously predicting early disease control (DC) and overall survival (OS). Of 1,234 patients with HCC enrolled from eight institutions and public databases, 832 ICI-treated patients were used for model development. ECOS-Net fused features using multi-head attention and generated early DC probabilities and OS risk scores. ECOS-DC achieved AUCs of 0.836, 0.822, and 0.817 in training, internal validation, and external test sets, outperforming clinical models (all p values < 0.05). ECOS-OS yielded C-indices of 0.730, 0.722, and 0.720, respectively. Integrated models also showed favorable external performance (early DC AUC: 0.825; OS C-index: 0.741). Patients with higher ECOS-DC probabilities had a higher likelihood of early DC, whereas those with higher ECOS-OS risk had shorter OS, with directionally consistent associations across most subgroups. Exploratory biological analyses suggested that the higher ECOS-DC probability and lower ECOS-OS risk groups were associated with immune-active tumor microenvironment features. Therefore, ECOS-Net shows potential as a non-invasive imaging-based risk stratification framework for simultaneously predicting early DC and OS in ICI-treated HCC patients.

PMID:42801546 | PMC:PMC13616327 | DOI:10.1002/advs.78005

J Inflamm Res. 2026 Sep 22;19:606503. doi: 10.2147/JIR.S606503. eCollection 2026.

ABSTRACT

BACKGROUND: Neutrophil extracellular traps (NETs) were key factors mediating inflammatory injury in acute pancreatitis (AP). To this end, there was an urgent need to identify precise and effective therapeutic targets that modulate NETs formation, providing new ideas for the prevention and treatment of AP pancreatitis injury.

GAP: To address this gap, we investigated the potential involvement of the myo-inositol metabolism in modulating NETs and inflammatory damage during AP.

METHODS: Multi-omics analysis identified myo-inositol metabolism as critical. We then established the in vitro NETs model using phorbol-12-myristate-13-acetate (PMA) to investigate the role and regulatory mechanism of inositol-3-phosphate synthase 1 (ISYNA1) on NETs formation. Finally, the findings were validated in the classic AP mouse model to verify the correlation between myo-inositol metabolism and AP pathogenesis.

RESULTS: Multiple omics analyses showed that the myo-inositol metabolic pathway is the most significant, and the key enzyme ISYNA1 involved in myo-inositol synthesis was significantly reduced. ISYNA1 was significantly downregulated in both the in vitro NETs model and in neutrophils infiltrating the pancreatic tissue of AP mice. Meanwhile, exogenous supplementation of ISYNA1 or myo-inositol significantly inhibited the NETs formation in vitro and inflammatory injury in AP mice. Mechanistically, downregulation of ISYNA1 led to reduced myo-inositol synthesis, thereby promoting NETs formation via modulation of the PI3K/AKT pathway.

CONCLUSION: ISYNA1 and myo-inositol metabolism were among the key links that regulated NETs formation and inflammatory injury in AP. Therefore, enhancing ISYNA1 and myo-inositol metabolism might serve as a potential intervention target for treating acute organ injury in AP.

PMID:42801157 | PMC:PMC13615823 | DOI:10.2147/JIR.S606503

Biomedicines. 2026 Aug 27;14(9):1919. doi: 10.3390/biomedicines14091919.

ABSTRACT

Immune checkpoint blockade has changed the management of several digestive system cancers, but its impact is highly context dependent. This review evaluates evidence for esophageal, gastric and gastroesophageal junction, colorectal, hepatocellular, biliary tract and gallbladder, and pancreatic cancers. Randomized phase III trials have established chemoimmunotherapy or dual-checkpoint strategies in advanced esophageal cancer, biomarker- and regimen-dependent first-line therapy in gastric cancer, PD-1-based therapy for MSI-H/dMMR colorectal cancer, atezolizumab-bevacizumab and STRIDE for unresectable hepatocellular carcinoma, and chemoimmunotherapy for advanced biliary tract cancer. Recent results also expand perioperative treatment: neoadjuvant checkpoint blockade produces high pathological response rates in dMMR colon cancer, adjuvant atezolizumab plus mFOLFOX6 improves disease-free survival in stage III dMMR colon cancer, and perioperative serplulimab improves event-free survival in PD-L1-positive resectable gastric cancer. These advances coexist with important negative findings. Pembrolizumab-containing therapy did not meet superiority end points in KEYNOTE-062, the initial adjuvant signal in IMbrave050 was not sustained, and unselected pancreatic ductal adenocarcinoma remains largely resistant to checkpoint blockade. Early vaccine, cellular, TIGIT, radiomics, spatial, and multi-omics studies remain hypothesis-generating and require external or randomized validation. Clinical interpretation should integrate evidence maturity, biomarker validity, immune-related toxicity, patient-reported outcomes, cost, access, and manufacturing demands rather than response rate alone.

PMID:42792661 | PMC:PMC13604390 | DOI:10.3390/biomedicines14091919

Arch Bronconeumol. 2026 Sep 25:S0300-2896(26)00318-2. doi: 10.1016/j.arbres.2026.08.007. Online ahead of print.

ABSTRACT

BACKGROUND: Highly effective CFTR modulator therapy with elexacaftor-tezacaftor-ivacaftor (ETI) has revolutionized clinical outcomes in cystic fibrosis (CF), yet its effects on gut and lung microbiota, especially at the functional level, are poorly understood.

METHODS: In a 12-month prospective study, we enrolled 35 clinically stable CF patients initiating ETI. Paired fecal and sputum samples, collected at baseline and after 12 months, were analyzed using shotgun metagenomics, metaproteomics, and short-chain fatty acid (SCFA) quantification. Multi-omics data were integrated with clinical parameters assessing lung, hepatic, pancreatic, and intestinal function.

RESULTS: ETI drove significant clinical improvements, including increased ppFEV₁, higher fecal elastase, and better nutritional status, despite persistent major lung pathogens and minimal changes in liver or intestinal inflammation markers. Microbiota composition showed limited shifts: alpha diversity was stable, and beta diversity changes accounted for only small variance in both compartments. However, butyrate-producing genera enriched in feces, while oropharyngeal taxa increased in sputum. Metaproteomics revealed broad downregulation of host neutrophil-driven inflammatory proteins; sputum additionally showed increased abundance of extracellular matrix-related proteins. Microbial proteins linked to carbohydrate/lipid metabolism, particularly butanoate pathways, increased in feces alongside a trend for higher butyrate. In sputum, formaldehyde dehydrogenase enzymes rose, indicating enhanced oxidative microbial metabolism.

CONCLUSIONS: ETI is associated with minimal compositional but substantial functional reprogramming in CF microbiota. These changes are accompanied by an increase in butyrate-producing taxa, attenuation of host pro-inflammatory pathways, and a shift in lung metabolism toward oxidation. Despite ongoing pathogenic colonization, these changes suggest CFTR modulation is associated with a less inflammatory, more stable host-microbiota ecosystem.

PMID:42791132 | DOI:10.1016/j.arbres.2026.08.007

Int J Biol Macromol. 2026 Sep 25:154618. doi: 10.1016/j.ijbiomac.2026.154618. Online ahead of print.

ABSTRACT

Inonotus obliquus is a medicinal fungus growing on birch bark. A neutral polysaccharide (IOP-W, M_w = 8.222 kDa) was isolated from its crude polysaccharides via sequential DEAE DE-52 cellulose column and Sephadex G-200 gel filtration column chromatography. IOP-W, composed primarily of galactose, glucose, and mannose, was structurally characterized by UV-Vis, FT-IR, GC-MS, and NMR as a glucan containing →4)-α-D-Glcp-(1→, →6)-β-D-Glcp-(1→, →3)-β-D-Glcp-(1→, →4,6)-α-D-Glcp-(1→, terminal α-D-Glcp, and β-D-Glcp reducing end. AFM confirmed its aggregated spherical morphology. IOP-W exerted antitumor activity against MIA PaCa-2 cells by modulating apoptosis and migration. Metabolomics revealed effects on amino acids, alkaloids, lipids, and nucleotides involving 20 pathways, while transcriptomic KEGG analysis showed regulation of MAPK, TNF, and p53 signaling. In vivo investigations employing small animal MRI technology have validated that tumor growth is significantly suppressed in animal models, accompanied by elevated spleen index and improved physiological parameters. Western blotting and immunohistochemistry revealed altered expression of Parp-1, p53, Bax/Bcl-2, p-ERK1/2, p-JNK1, NF-κB, vimentin, and MMP-9. These findings indicate that IOP-W inhibits pancreatic cancer via the p53/MAPK pathway, highlighting its potential as a fungal polysaccharide-based therapeutic candidate.

PMID:42790566 | DOI:10.1016/j.ijbiomac.2026.154618

Mol Cell Endocrinol. 2026 Sep 24:112920. doi: 10.1016/j.mce.2026.112920. Online ahead of print.

ABSTRACT

Clinical evidence suggests a complex link between inflammatory bowel disease and systemic glucose homeostasis, yet the underlying molecular mechanisms remain elusive. Here, we report that chronic ileitis, induced by dextran sulfate sodium (DSS) or IL10 deficiency under a high-fat diet(HFD), paradoxically ameliorates systemic glucose intolerance and preserves pancreatic β-cell mass in mice. Multi-omics analysis of ileal contents revealed a specific enrichment of Akkermansia muciniphila (AKK) and elevated levels of the metabolite 3-hydroxybutyrate (3-HB). Mechanistically, 3-HB activated HCAR2/CREB-associated signaling and increased NKX6.1 expression. NKX6.1 loss-of-function markedly attenuated 3-HB-induced insulin gene expression and glucose-stimulated insulin secretion, establishing NKX6.1 as an important functional mediator of the β-cell response to 3-HB. Furthermore, exogenous administration of 3-HB recapitulated these protective effects in diabetic mice. This study identifies a novel gut-islet axis where microbiota-derived 3-HB preserves β-cell functional identity via HCAR2 dependent regulation of NKX6.1, offering a potential therapeutic strategy for type 2 diabetes.

PMID:42785509 | DOI:10.1016/j.mce.2026.112920

Biochim Biophys Acta Mol Basis Dis. 2027 Jan;1873(1):168471. doi: 10.1016/j.bbadis.2026.168471. Epub 2026 Sep 24.

ABSTRACT

BACKGROUND: The global burden of metabolic-associated hepatocellular carcinoma (HCC) is increasing, with obesity emerging as a key causal factor. However, the molecular mechanisms linking lipid metabolic dysregulation to HCC progression and therapeutic vulnerability remain unclear.

METHODS: We analyzed Global Burden of Disease 2021 data to assess liver cancer burden attributable to metabolic risks from 1990 to 2021. Mendelian randomization was used to evaluate causal associations between metabolic traits and liver cancer risk. TCGA, GTEx, and GEO datasets were integrated to identify lipid stress-responsive regulators. Clinical relevance was assessed using public datasets and tissue microarray immunohistochemistry. Functional validation was performed in HCC cells and a high-fat diet-fed syngeneic mouse tumor model.

RESULTS: Liver cancer deaths and DALYs attributable to metabolic risks increased markedly from 1990 to 2021. Mendelian randomization showed that obesity-related traits, including BMI, waist circumference, and body fat percentage, were causally associated with liver cancer risk, whereas glycemic traits were not. Bioinformatics screening identified GPAT3 as a lipid metabolism regulator upregulated in HCC, induced by palmitic acid, associated with poor prognosis, and enriched in patients with higher BMI. Tissue microarray analysis confirmed increased GPAT3 protein expression in HCC and its association with higher BMI and GPX4 expression. GPAT3 depletion sensitized HCC cells to palmitic acid-induced ferroptosis, whereas Fer-1 rescue and GPAT3 overexpression supported its protective role. In vivo, FSG67 enhanced sorafenib-associated antitumor effects and increased tumor lipid peroxidation.

CONCLUSIONS: GPAT3 protects HCC cells from lipid stress-induced ferroptosis and represents a potential metabolic vulnerability in obesity-associated HCC.

PMID:42785105 | DOI:10.1016/j.bbadis.2026.168471

Transl Res. 2026 Sep 13:S1931-5244(26)00195-7. doi: 10.1016/j.trsl.2026.09.009. Online ahead of print.

ABSTRACT

Gemcitabine resistance remains a major barrier to effective therapy in pancreatic ductal adenocarcinoma (PDAC), and current combination regimens show potential to overcome this resistance. Here, we identify the mitochondrial ribosomal proteins MRPS22 and MRPL3 as key metabolic gatekeepers that maintain mitochondrial OXPHOS and pyrimidine metabolism, thereby promoting pancreatic cancer cell proliferation and chemoresistance. Across independent cohorts, high MRPS22/MRPL3 expression associates with poorer survival. Depletion of either gene in PDAC curtailed cell proliferation and xenograft growth, which might be due to an impaired mitochondria function, including destabilized respiratory super-complex assembly, diminished ATP production, and increased oxidative stress. Multi-omics profiling revealed a broad reduction of central-carbon intermediates and a pronounced blockade of de novo pyrimidine synthesis at the dihydroorotate dehydrogenase (DHODH) node. MRPS22 depletion hampered nucleotide-pool generation, and exogenous deoxynucleotides partially rescued PDAC cell growth when MRPs were knocked down. Pharmacologic OXPHOS inhibition increased gemcitabine sensitivity, whereas gemcitabine-resistant derivatives exhibited heightened OXPHOS activity and upregulated mitochondrial ribosomal programs. Co-targeting OXPHOS (antimycin A) or DHODH (brequinar) with gemcitabine produced Loewe synergy in vitro and suppressed growth of gemcitabine-resistant xenografts without affecting body weight. Collectively, these findings established MRPS22/MRPL3 as translation-level drivers of PDAC metabolic fitness and nominate OXPHOS/DHODH blockade as a rational combination strategy to overcome gemcitabine resistance.

PMID:42732873 | DOI:10.1016/j.trsl.2026.09.009

Dig Liver Dis. 2026 Sep 12:S1590-8658(26)00920-5. doi: 10.1016/j.dld.2026.08.021. Online ahead of print.

ABSTRACT

The quality of biological samples is a major determinant of analytical reliability and translational relevance in patients with pancreatic ductal adenocarcinoma (PDAC). However, variability in specimen procurement, handling, transport, processing, and storage can substantially affect tissue integrity and the robustness of downstream analyses. This paper, promoted by the Pathology and Basic Science Task Force of the Italian Association for the Study of the Pancreas (AISP), brings together experts in pathology, molecular biology, translational research, medical oncology, and gastroenterology to provide practical recommendations for the collection, handling, and pre-analytical management of biological samples. Draft recommendations were discussed during dedicated working group meetings and approved by consensus among all authors, supported by key literature. The document identifies the biological specimen as the critical link between patient care, pathology, and research, and provides guidance for clinicians and professionals involved in sample procurement and processing. By addressing the requirements of different analytical platforms, including genomics, organoid generation, immunophenotyping, pharmacogenomics, and multiplex/spatial analyses, this paper aims to reduce pre-analytical variability, improve diagnostic accuracy, and enhance the clinical and translational value of molecular investigations in pancreatic cancer. Standardised procedures across centres may facilitate comparable data collection, support multicentre studies, and strengthen collaboration between clinicians, pathologists, and research laboratories.

PMID:42731958 | DOI:10.1016/j.dld.2026.08.021

FASEB J. 2026 Sep 30;40(18):e72296. doi: 10.1096/fj.202603069R.

ABSTRACT

Pancreatic cancer (PC) presents a significant global health challenge because of its high mortality rate, highlighting the urgent requirement for effective early diagnostic and therapeutic strategies. This study examined the function of phenylalanine metabolism in PC and developed a high-accuracy diagnostic model by integrating metabolomics, Mendelian randomization (MR), and machine learning (ML) algorithms. Initially, MR analysis was conducted on 55 plasma metabolites, revealing a significant causal link between phenylalanine and PC. Utilizing GeneCards and public transcriptomic databases, we determined eight differentially expressed genes (DEGs) in PC associated with phenylalanine. Based on these genes, we utilized 12 ML algorithms, totaling 113 combinations, to select the optimal diagnostic model. We applied Shapley Additive exPlanations (SHAP) for feature interpretation and constructed a prognostic nomogram with strong predictive performance by incorporating clinical variables. Furthermore, immune infiltration analysis demonstrated strong connections between these key genes and specific immune cell populations. Based on the SHAP value, we conducted single-cell RNA sequencing (scRNA-seq) data and simulated gene knockout analyses using SLC6A14 as the key gene. Drug target prediction-guided molecular docking and molecular dynamics simulations, focusing on the core gene SLC6A14, confirmed the high binding stability of candidate compounds. Finally, in vitro cell experiments quantitative real-time PCR (RT-qPCR) verified the expression trends of the key genes in PC cell lines. In conclusion, this study successfully developed an ML diagnostic model with high biological interpretability. This analysis aims to identify biomarkers related to phenylalanine metabolism and potential therapeutic drugs for PC, offering new strategies for personalized targeted therapy of PC.

PMID:42730913 | PMC:PMC13570651 | DOI:10.1096/fj.202603069R

Ann Surg Oncol. 2026 Sep 12. doi: 10.1245/s10434-026-20366-0. Online ahead of print.

ABSTRACT

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited long-term survival despite advances in surgery and systemic therapy.

PATIENTS: The population of interest comprises patients with PDAC characterized by targetable molecular alterations and biologically distinct transcriptomic subtypes.

METHODS: We performed a narrative review of landmark and contemporary clinical trials, translational studies, and emerging molecular-classification platforms relevant to precision oncology in PDAC.

RESULTS: Growing understanding of PDAC molecular biology has identified putative genetic mutations, including homologous recombination repair deficiency, mismatch repair deficiency, and mutated KRAS, enabling the development of targeted therapies and precision treatment strategies. Concurrently, transcriptomic profiling has revealed biologically distinct molecular subtypes associated with differences in prognosis and therapeutic response. Emerging tools such as molecular classifiers, deep learning models, and multiomic platforms may further refine patient selection and treatment personalization.

CONCLUSIONS: This review highlights contemporary efforts of novel targeted therapies, ongoing advances in molecular subtyping, and the evolving role of precision oncology in improving outcomes for patients with PDAC.

PMID:42732021 | DOI:10.1245/s10434-026-20366-0

Front Endocrinol (Lausanne). 2026 Aug 27;17:1938241. doi: 10.3389/fendo.2026.1938241. eCollection 2026.

ABSTRACT

Type 1 diabetes (T1D), which commonly presents in childhood or adolescence, is an autoimmune disease in which immune-mediated destruction of pancreatic β-cells leads to absolute or near-absolute insulin deficiency and lifelong dependence on insulin administration. During adolescence, pubertal changes and increased insulin requirements can worsen glycemic instability and raise the risk of vascular complications, such as cardiovascular disease. Although hyperglycemia promotes vascular injury, different early vascular phenotypes in adolescents with similar hemoglobin A₁c (HbA₁c) levels suggest that additional mechanisms may influence vascular risk. Insulin resistance (IR) may be an important contributor because insulin sensitivity declines during puberty, and this decline is associated with oxidative stress, altered endothelial signaling, inflammation, and adiposity. However, establishing a causal relationship between IR and early vascular injury in T1D remains challenging. This review examines the link between IR and early vascular injury in adolescents with T1D and emphasizes endothelial dysfunction, arterial stiffness, and biomarkers that may connect metabolic stress to vascular damage. Evidence from metabolic, endothelial, inflammatory, omics-based, and imaging studies supports an association between IR, inflammatory pathways, endothelial injury, and impaired vascular repair. Overall, IR, inflammatory, endothelial, and vascular imaging measures may complement HbA₁c when studying vascular risk in adolescents with T1D. Whether they provide additional diagnostic or prognostic value beyond HbA₁c is still unknown.

PMID:42725052 | PMC:PMC13559969 | DOI:10.3389/fendo.2026.1938241