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

Front Endocrinol (Lausanne). 2026 Aug 27;17:1782791. doi: 10.3389/fendo.2026.1782791. eCollection 2026.

ABSTRACT

Neuroendocrine neoplasms (NENs) are biologically heterogeneous tumors in which differentiation/grade and hormonal functionality are intersecting but non-equivalent axes. This review focuses on functional and non-functional well-differentiated neuroendocrine tumors (NETs), principally gastroenteropancreatic and pancreatic NETs, and critically evaluates how site, lineage, stage, tumor burden, genomic and epigenetic alterations, immune-stromal remodeling, metabolic adaptation, microbiome-associated signals, and treatment pressure converge on metastasis and recurrence. Apparent outcome differences by functionality are inconsistent after clinicopathological adjustment: non-functional presentation is often enriched for delayed diagnosis and adverse features, whereas functional subtypes range from typically indolent insulinomas to clinically aggressive hormone-producing tumors. We reconcile these observations through a layered model in which lineage-defining alterations and chromatin/telomere programs establish cellular state; signaling and metabolic plasticity enable stress adaptation; and hypoxia, angiogenesis, immune cells, fibroblasts, extracellular matrix, and therapy create selective niches for dissemination and relapse. We also define computational strategies for heterogeneous multi-omics integration and a staged biomarker-validation pathway. Evidence remains dominated by pancreatic NETs, and causal support is weakest for microbiome-functionality relationships and several proposed cross-omic links. A spectrum-based framework is therefore most useful when it generates testable, site- and grade-specific hypotheses rather than treating functionality as an isolated prognostic variable.

PMID:42724134 | PMC:PMC13559159 | DOI:10.3389/fendo.2026.1782791

PLoS Comput Biol. 2026 Sep 10;22(9):e1014735. doi: 10.1371/journal.pcbi.1014735. Online ahead of print.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC), with a 12% 5-year survival rate, is the most aggressive type of cancer. Early diagnosis for this pathology is rare, and conventional treatments such as surgery, radio- or chemotherapy, have little to no effect on reducing mortality. Machine learning (ML) approaches could be used to identify biomarkers that help clinicians stratify patients and improve treatment outcomes. However, most ML techniques perform poorly with incomplete data, which is usually the case in real-world settings, often forcing researchers to discard valuable information. In this study, unsupervised ML algorithms capable of dealing with missing modalities were applied to incomplete multi-omics data from PDAC patients to identify clinically meaningful patient subgroups. Through a large-scale clustering benchmark including six omics layers, we discovered two novel subgroups with statistically significant differences in survival and recurrence after surgery, particularly within the first two years, when most patient deaths occur, as well as distinct tumor mutational burden. Comprehensive multi-omics analyses revealed substantial molecular differences between patients in both groups, identified three methylation biomarkers to stratify patients, and highlighted dysregulation in key oncogenic pathways. Importantly, the identified groups are different from previous PDAC classifications, both in their patient composition, prognosis, and in the oncogenic gene pathway profiles exhibited. Using an independent cohort, we further demonstrated that both the prognostic value of these subtypes and their underlying biological characteristics are reproducible. These results could lead to better stratified treatment regimens to improve the prognosis of PDAC patients.

PMID:42721202 | DOI:10.1371/journal.pcbi.1014735

Mol Omics. 2026 Sep 10:aaiag022. doi: 10.1093/molecular-omics/aaiag022. Online ahead of print.

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-related proteins as recurrently altered across mutant alleles, while phosphoproteomic data confirmed robust ERK1/2 activity and suppression of DYRK kinase substrates by mutant KRAS expression. Importantly, no robust mutant allele-specific molecular programs were identified in our KRAS-reconstituted cell lines. 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.

PMID:42720273 | DOI:10.1093/molecular-omics/aaiag022

Biofactors. 2026 Sep-Oct;52(5):e70150. doi: 10.1002/biof.70150.

ABSTRACT

Gastrointestinal malignancies, including gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, remain major causes of cancer-related morbidity and mortality worldwide. Although chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic malignancies, its efficacy in gastrointestinal solid tumors remains limited by antigen heterogeneity, insufficient trafficking and infiltration, immunosuppressive tumor microenvironments, on-target off-tumor toxicity, and adaptive resistance. In this review, we summarize the current landscape of CAR-T therapy in gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer, with a focus on representative target antigens and emerging biomarker strategies. We further discuss two major categories of biomarkers: target antigen-related biomarkers and conventional dynamic biomarkers, including serum tumor markers, cytokine changes, CAR-T expansion kinetics, and antigen-loss monitoring. In addition, we highlight how single-cell ribonucleic acid sequencing and spatial transcriptomics provide complementary insights into cellular states, immune exhaustion, stromal barriers, and spatially restricted immune exclusion. By integrating these multi-omics approaches with biomarker-guided patient stratification and next-generation CAR-T engineering, gastrointestinal solid tumor CAR-T therapy may evolve from empirical optimization toward mechanism-driven and precision-guided clinical translation.

PMID:42717494 | PMC:PMC13558850 | DOI:10.1002/biof.70150

Free Radic Biol Med. 2026 Sep 9;256:441-460. doi: 10.1016/j.freeradbiomed.2026.09.006. Online ahead of print.

ABSTRACT

Gestational diabetes mellitus (GDM) is a common pregnancy complication with a rising global prevalence, posing serious short-term and long-term health threats to both mothers and offspring. This review repositions GDM as a systemic disorder in which oxidative stress acts as a proposed mechanistic hub, linking upstream risk factors to downstream pathophysiology. We first examine how "upstream" factors-including genetic susceptibility, pre-conception status, and environmental exposures-converge to promote a state of pathological redox imbalance. We then examine key mechanistic pathways through which oxidative stress is thought to contribute to systemic insulin resistance and pancreatic β-cell failure, highlighting novel pathways involving intercellular communication via tunneling nanotubes and exosomes. Furthermore, we explore the downstream cascade, where oxidative stress may program maternal accelerated biological aging and multi-organ offspring disease trajectories through nuclear epigenetic programming and mitochondrial dysfunction programming, leaving what has been termed a persistent "metabolic memory". Consequently, this review evaluates emerging strategies that target oxidative stress for early prediction and precision intervention. Early prediction models based on direct redox biomarkers and multi-omics signatures hold potential to shift diagnosis from late-gestation oral glucose tolerance test (OGTT) to first-trimester risk stratification. Current supporting evidence draws from human epidemiological associations, ex vivo placental analyses, and experimental models. However, direct causal and interventional validation in pregnant women remains limited. Integrating targeted redox risk stratification and precision interventions into a life-course clinical framework may help interrupt the intergenerational transmission of metabolic disease initiated by GDM.

PMID:42716407 | DOI:10.1016/j.freeradbiomed.2026.09.006

Chin J Cancer Res. 2026 Aug 30;38(4):480-500. doi: 10.21147/j.issn.1000-9604.2026.04.08.

ABSTRACT

OBJECTIVE: Breast cancer remains a leading cause of global cancer mortality, characterized by profound heterogeneity. While immune checkpoint blockade (ICB) has transformed oncology, its efficacy in breast cancer is often hindered by "immune-cold" microenvironments and immune exclusion. Programmed cell death (PCD) is a critical regulator of tumor immune microenvironment (TIME). However, its role in the breast cancer immune microenvironment remains poorly understood.

METHODS: We integrated multi-omics data from six breast cancer cohorts (N=3,764) to develop a programmed cell death learning signature (PCDsig) using over 100 machine learning combinations. The model was benchmarked against 29 published signatures. Single-cell transcriptomic analysis decoded the immune landscape and cellular crosstalk. The role of adaptor-related protein complex 1 subunit sigma 1 (AP1S1) was validated through a clinical cohort, in vitro functional assays, and in vivo syngeneic mouse models.

RESULTS: PCDsig significantly stratified patient prognosis across all cohorts, consistently outperforming 29 existing models. High PCDsig scores correlated with immune-excluded phenotypes, reduced CD8+ T cell infiltration, and lower immunophenoscores. Single-cell analysis revealed that high-PCDsig tumors utilize vascular endothelial growth factor A (VEGFA) signaling to foster an immunosuppressive microenvironment. AP1S1 was identified as the core driver of immune exclusion. And our clinical cohort supported the immune exclusion effect of AP1S1. AP1S1 knockdown impaired tumor progression in vitro and fundamentally remodeled the tumor immune ecosystem in vivo. Combining AP1S1 inhibition with anti-programmed cell death ligand 1 (anti-PD-L1) therapy exerted profound synergistic effects, driven by massive infiltration and functional activation of cytotoxic Granzyme B (GZMB)+CD8+ T cells.

CONCLUSIONS: Our study establishes the PCDsig we developed is a potential prognostic and predictive biomarker for breast cancer. We provide the first evidence of AP1S1 as a core immunomodulatory oncogene that mediates immune exclusion. Targeting AP1S1 represents a highly promising strategy to sensitize cold breast tumors to ICB, offering a new perspective for precision immunotherapy.

PMID:42712842 | PMC:PMC13551362 | DOI:10.21147/j.issn.1000-9604.2026.04.08

Theranostics. 2026 Jul 29;16(15):8478-8500. doi: 10.7150/thno.131237. eCollection 2026.

ABSTRACT

BACKGROUND: The αvβ6 and αvβ8 integrins are upregulated in many solid-tumors and drive local activation of transforming growth factor-β (TGFβ), promoting immune evasion and resistance to immune checkpoint blockade. The chromogranin A-derived peptide 4Δ targets the RGD-binding site of αvβ6/αvβ8 and inhibits integrin-dependent TGFβ-activation. We investigated whether 4Δ-derived peptibodies can deliver cytotoxic drugs to cancer cells and enhance immune checkpoint inhibitors (ICIs) activity.

METHODS: Peptide 4Δ was genetically fused to the Fc domains of murine and human IgG1 to generate the peptibodies 4ΔmFc and 4ΔhFc. Integrin-binding properties and inhibition of TGFβ activation were characterized using biochemical and cell-based assays. Peptibody internalization and lysosomal trafficking were analyzed by live-cell/confocal microscopy. Cytotoxic activity of peptibodies complexed with anti-Fc antibodies coupled to anticancer drugs was evaluated using αvβ6/αvβ8-positive and -negative cancer cells. Pharmacokinetics and antitumor activity of 4ΔmFc, alone or in combination with an anti-PD-L1 antibody, were evaluated in murine fibrosarcoma and mammary carcinoma models.

RESULTS: 4ΔmFc and 4ΔhFc bound αvβ6 and αvβ8 with sub-nanomolar affinity. Both compounds selectively recognized αvβ6/αvβ8-positive tumor cells, as well as human pancreatic, lung, and colon carcinomas sections. 4ΔmFc and 4ΔhFc efficiently inhibited TGFβ activation, underwent efficient internalization, and trafficked to lysosomes. 4ΔhFc enabled delivery of cytotoxic payloads to αvβ6/αvβ8-positive cells, including MMAE, MMAF, DM1, PBD, or DX8951. 4ΔmFc delayed the growth of fibrosarcomas and improved mice survival in the mammary adenocarcinoma model when combined with an anti-PD-L1 mAb (immune checkpoint inhibitor), without overt toxicity.

CONCLUSION: These peptibodies represent a dual-selective αvβ6/αvβ8-targeting platform that couples potent blockade of integrin-dependent TGFβ activation with efficient, selective delivery of cytotoxic payloads to cancer cells. These properties, together with the observed synergism with anti-PD-L1 mAbs, suggest their potential use as ligands for delivering cytotoxic agents to tumors, while concomitantly modulating the TGFβ-driven immunosuppressive microenvironment, either alone or in combination with ICIs.

PMID:42708025 | PMC:PMC13549134 | DOI:10.7150/thno.131237

Gut. 2026 Sep 7:gutjnl-2025-337414. doi: 10.1136/gutjnl-2025-337414. Online ahead of print.

ABSTRACT

BACKGROUND: Neutrophils are increasingly recognised as immunosuppressive drivers of hepatocellular carcinoma (HCC), yet their persistence in the oxidative, lipid-rich tumour microenvironment remains poorly understood.

OBJECTIVE: To elucidate the metabolic and molecular programmes that enable tumour-associated neutrophils (TANs) to resist ferroptosis and sustain immunosuppression in HCC.

DESIGN: We employed human HCC samples, multiple murine HCC models, transcriptomic and lipidomic profiling, genetic loss-of-function systems and therapeutic interventions. Ferroptosis sensitivity, lipid metabolic rewiring and immunological consequences of TANs were systematically evaluated across models and validated in patient datasets and biospecimens.

RESULTS: TANs in human HCC and mouse models exhibit pronounced lipid accumulation and oxidative stress compared with peripheral neutrophils. Multi-omic profiling revealed that TANs are enriched for lipid-binding gene programmes and undergo rewiring towards sphingolipid and unsaturated fatty acid metabolism. We identified triggering receptor expressed on myeloid cells 2 (TREM2) as a key lipid-sensing receptor selectively expressed in TANs. Functional deletion of TREM2 reprogrammed the tumour immune microenvironment, restoring CD8⁺ T cell activity and suppressing HCC progression. Mechanistically, tumour-derived sphingosine-1-phosphate (S1P) activates TREM2, triggering nuclear factor erythroid 2-related factor 2 (NRF2)-mediated transcription of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), thereby promoting ferroptosis resistance. TREM2 expression is transcriptionally induced by granulocyte-macrophage colony-stimulating factor-signal transducer and activator of transcription 3 (GM-CSF-STAT3) signalling. Genetic deletion of TREM2, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated knockout of sphingosine kinase 1/2 (SPHK1/2) in tumour cells, or pharmacological inhibition of S1P synthesis disrupts this protective lipid-immune circuit, sensitises TANs to ferroptosis and restricts tumour growth. Therapeutically, a peptide-based TREM2 inhibitor reprogrammes TANs, restores CD8⁺ T cell function and enhances anti-programmed cell death protein 1 (PD-1) immunotherapy efficacy. Clinically, TREM2⁺ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in HCC tumours, correlate with SPHK1/2 expression and T cell dysfunction and associate with poor patient prognosis.

CONCLUSION: Our study uncovers the S1P-TREM2-NRF2 axis as a critical metabolic-immune circuit that preserves neutrophil survival and immunosuppressive function in HCC. Targeting this lipid-dependent ferroptosis resistance pathway offers a promising therapeutic strategy to overcome immunotherapy resistance in liver cancer.

PMID:42705697 | DOI:10.1136/gutjnl-2025-337414

Phytomedicine. 2026 Aug 26;161:158760. doi: 10.1016/j.phymed.2026.158760. Online ahead of print.

ABSTRACT

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) harbors TP53 mutations at high frequency, yet therapeutic strategies that specifically target mutant p53 remain limited.

PURPOSE: This study aimed to identify S100A6, a calcium-binding protein frequently upregulated in TP53-mutant PDAC, as a critical regulator of mutant p53 stability and tumor progression, and to explore potential S100A6-targeting agents for therapeutic intervention.

METHODS: We integrated computer-assisted drug screening with transcriptomics, acetylation omics, and molecular biology techniques to identify Agrimol B (AgrB), a bioactive compound derived from the traditional Chinese herb Agrimonia pilosa Ledeb., as a potential S100A6-targeting agent.

RESULTS: High S100A6 expression was closely associated with poor prognosis in patients with TP53-mutant PDAC, whereas S100A6 depletion markedly suppressed PDAC cell growth and metastatic potential. Mechanistically, AgrB enhanced the interaction between S100A6 and the deacetylase HDAC2, leading to reduced acetylation of mutant p53 at lysine 382. This disruption activated autophagy-dependent cell death and thereby inhibited PDAC progression.

CONCLUSION: Our findings reveal an S100A6-HDAC2-mutant p53 acetylation axis that regulates TP53-mutant pancreatic tumorigenesis, providing mechanistic evidence supporting S100A6 as a therapeutic vulnerability and highlighting AgrB as a promising natural-product-derived candidate for further development against this aggressive malignancy.

PMID:42700714 | DOI:10.1016/j.phymed.2026.158760

Anticancer Agents Med Chem. 2026 Aug 24. doi: 10.2174/0118715206400800251128055423. Online ahead of print.

ABSTRACT

Gastrointestinal (GI) cancers-including colorectal, gastric, pancreatic, and esophageal malignancies- remain among the most prevalent and lethal cancers worldwide, largely due to their biological complexity and late-stage diagnosis. This narrative review examines the critical role of biomarkers in advancing personalized treatment strategies for GI cancers. Key diagnostic, prognostic, and predictive biomarkers, such as KRAS, HER2, PD-L1, microsatellite instability (MSI), and circulating tumor DNA (ctDNA), are discussed about their application in clinical decision-making. The review highlights biomarker-driven approaches across different GI cancer types, demonstrating how molecular profiling informs early detection, treatment selection, and monitoring of therapeutic response. Recent technological advances-including liquid biopsy, next-generation sequencing, and multi-omics integration- have expanded biomarker discovery and enhanced clinical utility. Challenges in implementing biomarker testing, such as variability in expression, lack of standardization, and limited accessibility, are also addressed. Overall, this article emphasizes the transformative potential of biomarkers to tailor therapy, improve patient outcomes, and shape the future of precision oncology in gastrointestinal cancers.

PMID:42693869 | DOI:10.2174/0118715206400800251128055423

Nat Commun. 2026 Aug 7;17(1):9491. doi: 10.1038/s41467-026-76495-3.

ABSTRACT

Cancer-associated fibroblasts comprise diverse functionally distinct cellular subsets, with certain subpopulations exerting pivotal influence in shaping the pancreatic cancer immune microenvironment. Here we show that Lin28b⁺ cancer-associated fibroblasts contribute to establishing an immunologically cold tumor microenvironment in pancreatic ductal adenocarcinoma. Mechanistically, Lin28b directly binds to STING mRNA and promotes its degradation, thereby suppressing STING expression and downstream type I interferon signaling. Loss of Lin28b in cancer-associated fibroblasts activates the cGAS-STING-interferon signaling cascade, enhancing dendritic cell antigen presentation and CD8⁺ T cell cytotoxic function. Importantly, genetic inhibition of Lin28b in cancer-associated fibroblasts enhances sensitivity to anti-PD-L1 immune checkpoint blockade therapy. These findings reveal that targeting the Lin28b-STING axis represents a promising therapeutic strategy for overcoming the intrinsic resistance of pancreatic ductal adenocarcinoma to immunotherapy.

PMID:42693143 | PMC:PMC13542369 | DOI:10.1038/s41467-026-76495-3

Signal Transduct Target Ther. 2026 Sep 4;11(1):363. doi: 10.1038/s41392-026-02936-6.

ABSTRACT

Metabolic reprogramming forms the foundation of immune effector functions and the regulation of inflammation. As a pivotal node connecting the tricarboxylic acid cycle to immune signaling, the IRG1/ACOD1 and itaconate axes play a central role in coordinating inflammatory tone and redox balance. Itaconate, generated through the decarboxylation of cis aconitate, acts as an immunometabolic brake that engages multiple regulatory pathways to sustain the dynamic equilibrium between inflammation and tissue homeostasis. Across a broad spectrum of pathological conditions, including infectious diseases, metabolic disorders, ischemia‒reperfusion injury, neurodegenerative diseases, autoimmune disorders, and cancers, itaconate and its derivatives generally exert anti-inflammatory and cytoprotective effects. However, within specific microenvironments, these molecules may also be exploited by pathogens to evade immune clearance or promote immunosuppressive and protumorigenic responses. Future studies should further elucidate tissue- and lineage-specific functions, define bidirectional regulatory mechanisms, and optimize the pharmacokinetic properties of itaconate derivatives. With the advancement of multiomics integration, systems immunology, rational drug design, and engineered itaconate delivery technologies, the IRG1/ACOD1-itaconate axis and derivative-based therapeutic strategies are poised to emerge as key metabolic checkpoints and therapeutic targets in inflammatory-, metabolic-, immune-, and cancer-related diseases.

PMID:42693110 | PMC:PMC13542262 | DOI:10.1038/s41392-026-02936-6

World J Microbiol Biotechnol. 2026 Sep 3;42(9):514. doi: 10.1007/s11274-026-05249-6.

ABSTRACT

Obesity, Type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) represent interconnected global health problems that can be caused by dietary factors, life-style changes and alterations in the gut microbiota composition. While numerous reports highlight the connections between microbial taxa and the host diseases, the underlying molecular mechanisms behind the impact of metabolites on the disease development remain poorly defined. In this review, the connection between four interrelated pathways through which metabolites from the gut microbiota affect metabolic disease are highlighted. They include (i) reprogramming of host metabolism through histone deacetylase (HDAC) inhibition and remodeling of the chromatin structure; (ii) mitochondrial dysfunction and disturbance in redox balance; (iii) hijacking of receptors and pathway biased crosstalk (FFAR2/3, GPR109A, FXR, TGR5, AhR, TLR4) and (iv) disruption of intestinal barrier and induction of metabolic endotoxemia. Such axes form a feedback network through which the inflammation and insulin resistance spread over the entire gut-adipose-liver-pancreas-muscle axis. The effect of the metabolites is very context-dependent since it relies on the concentration threshold, receptor bias, disease state and interaction between the host genotype and enterotype. The translational applications include composite metabolite biomarkers, enterotype-based therapeutic approaches, bacterial extracellular vesicles and machine learning approaches to develop multi-omics data analysis resulting in generation of a digital twin model.

PMID:42690471 | DOI:10.1007/s11274-026-05249-6

Hematol Oncol Clin North Am. 2026 Oct;40(5):807-829. doi: 10.1016/j.hoc.2026.05.021.

ABSTRACT

Precision medicine is used to treat gastrointestinal malignancies including esophageal, gastric, small bowel, colorectal, and pancreatic cancers. Cutting-edge assays to detect and treat these cancers are active areas of research and will soon become standard of care. Colorectal cancer is a prime example of precision oncology as disease site is no longer the final determinate of treatment. Here, the authors describe how leveraging an understanding of tumor biology translates to individualized patient care using evidence-based practices.

PMID:42686330 | DOI:10.1016/j.hoc.2026.05.021

J Vis Exp. 2026 Sep 1;(235). doi: 10.3791/73747.

ABSTRACT

Liver resection and liver transplantation remain cornerstone treatments for many hepatobiliary diseases, yet postoperative infection, impaired liver regeneration, and post-hepatectomy liver failure (PHLF) remain serious complications. Perioperative stressors can disrupt the gut-liver axis by altering the intestinal microbiota, epithelial barrier integrity, microbial metabolites, bile acid signaling, and host immunity. This review examines how these alterations relate to clinical outcomes and evaluates evidence for microbiota-targeted interventions, including probiotics, synbiotics, nutritional optimization, antibiotic stewardship, bile acid modulation, and emerging multiomics strategies. We distinguish liver resection from living-donor and deceased-donor liver transplantation because the patient populations, graft or remnant anatomy, ischemia-reperfusion exposures, immune status, and outcome definitions differ. Clinical evidence most consistently supports selected pro-/synbiotic strategies for reducing postoperative infection in higher-risk settings, whereas microbiome-based prediction of PHLF, fecal microbiota transplantation (FMT), bile acid-directed therapy, and precision multiomics-guided pathways remain investigational. Future work should use transparent literature identification, standardized perioperative protocols, risk-defined populations, external validation, and prospective multicenter trials. A better understanding of gut-liver interactions may help preserve beneficial host-microbial signals while limiting translocation and inflammation during recovery.

PMID:42683887 | DOI:10.3791/73747