Front Oncol. 2026 Aug 25;16:1842715. doi: 10.3389/fonc.2026.1842715. eCollection 2026.

ABSTRACT

Poorly cohesive gastric cancer (PCGC) represents a biologically distinct subtype of gastric cancer, characterized by diffuse growth, marked intratumoral heterogeneity, and a consistently worse prognosis compared with other histological subtypes. Despite advances in pathological classification and molecular profiling, treatment strategies remain largely independent of histological subtype, and no specific therapeutic approaches have been established for PCGC. In this review, we summarize current evidence on the biological features, diagnostic challenges, and emerging therapeutic strategies, with a focus on novel targeted agents and innovative treatment platforms. Recent years have witnessed the development of therapies directed against specific molecular targets, including HER2, PD-L1, CLDN18.2, FGFR2b, and TROP2, as well as the introduction of antibody-drug conjugates and bispecific antibodies, progressively expanding the therapeutic landscape of gastric cancer. However, their clinical impact in poorly cohesive tumors remains to be fully defined. In parallel, advances in digital pathology, artificial intelligence, and multi-omics approaches are providing new opportunities to improve diagnostic reproducibility, refine prognostic stratification, and support personalized treatment strategies by integrating histomorphological and molecular tumor features. Overall, the convergence of novel therapeutic strategies and advanced diagnostic technologies may pave the way toward a more precise and biologically informed management of PCGC, although further validation and integration into clinical practice are required.

PMID:42713041 | PMC:PMC13550965 | DOI:10.3389/fonc.2026.1842715

Cell Death Differ. 2026 Sep 8. doi: 10.1038/s41418-026-01867-7. Online ahead of print.

ABSTRACT

Gastric cancer (GC) displays marked heterogeneity under the Lauren classification, yet the metabolic determinants of subtype divergence remain unclear. Here, we identify Malonyl-CoA:ACP transacylase (MCAT), a Lauren subtype-associated gene encoding a key mitochondrial fatty acid synthesis (mtFAS) enzyme, as a subtype-specific tumor suppressor in GC. Integrative multi-omics profiling revealed that MCAT expression is enriched in intestinal-type GC and correlates with favorable prognosis. Mechanistically, MCAT overexpression drives metabolic reprogramming through mitochondrial free fatty acid overload, suppressing β-oxidation while elevating mitochondrial reactive oxygen species (ROS), which triggers P53 phosphorylation at Ser15. This event concurrently activates PINK1/Parkin-mediated mitophagy and suppresses the SLC7A11/GPX4 axis to induce ferroptosis. Genetic rescue experiments confirmed that P53-Ser15 phosphorylation is essential for both mitophagy and ferroptosis induction. Endogenous MCAT levels are sufficient to determine basal ROS/P53/mitophagy/ferroptosis axis activity, and knockdown in high-expressing cells reverses these phenotypes, supporting a physiological, threshold-dependent role. In vivo, MCAT overexpression suppresses tumor growth and enhances mitophagy and ferroptosis markers. Collectively, these findings establish MCAT as a metabolic switch that links mtFAS to ROS/P53-dependent cell death, providing a potential biomarker and therapeutic target for GC.

PMID:42711380 | DOI:10.1038/s41418-026-01867-7

Gastroenterol Res Pract. 2026 Sep 7;2026:3413458. doi: 10.1155/grp/3413458. eCollection 2026.

ABSTRACT

Helicobacter pylori-associated gastritis (HPAG) is a chronic inflammatory condition of the gastric mucosa caused by Helicobacter pylori infection, serving as the core etiological factor for peptic ulcers and gastric precancerous lesions. Given the persistently high global infection rates and the escalating burden of antibiotic resistance, conventional eradication therapies are encountering significant challenges. This article systematically delineates the molecular pathogenic mechanisms underlying HPAG, encompassing bacterial virulence factors, host immune responses, aberrant signaling pathways, oxidative stress, epigenetic regulation, and mucosal barrier damage. Building upon this foundation and in alignment with international mainstream diagnostic and therapeutic guidelines, we summarize the research progress of traditional Chinese medicine (TCM) interventions from a novel perspective of microecological homeostasis regulation. Specifically, we clarify the multifaceted roles of TCM monomers and formulas in immunomodulation, mucosal repair, and antibacterial synergism. By systematically synthesizing existing evidence from TCM studies, we construct a whole-course TCM intervention framework for HPAG that integrates "susceptibility prevention, active treatment, and posteradication repair." Furthermore, we critically analyze the current clinical translation bottlenecks and the limitations inherent in the "black-box" research paradigm of TCM monomers and formulas, and propose future research directions driven by multiomics technologies. This work provides both theoretical support and practical references for precise integrated Chinese and Western medicine diagnosis and treatment of HPAG.

PMID:42707495 | PMC:PMC13548316 | DOI:10.1155/grp/3413458

J Ethnopharmacol. 2026 Sep 5;374(Pt 1):122370. doi: 10.1016/j.jep.2026.122370. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Wuwei Huanglian Wan (WWHLW) is a traditional Tibetan medicine formula developed by Tibetan physician Takpe Pingcuo and officially documented in the Ministry of Health Drug Standards for Tibetan Medicines (Volume I, 1995). It has long been used for the treatment of gastrointestinal disorders, particularly conditions associated with gastrointestinal discomfort and inflammation. Given the overlap between its traditional indications and the clinical manifestations of H. pylori-associated gastritis (HAG), WWHLW represents a promising candidate for the management of H. pylori infection and related gastric inflammation. In addition, several constituent herbs of WWHLW have demonstrated anti-H. pylori and anti-inflammatory activities, providing a pharmacological basis for further investigating its therapeutic effects.

AIM OF THE STUDY: This study aimed to systematically evaluate the therapeutic effects of WWHLW against H. pylori infection and HAG, and to explore the biological processes associated with these effects through integrated multi-omics and experimental validation.

MATERIALS AND METHODS: The therapeutic effects of WWHLW were evaluated through in vitro antibacterial assays and an H. pylori-infected mouse model. UHPLC-HRMS/MS was employed for chemical profiling and identification of serum-absorbed constituents. Serum metabolomics, 16S rRNA gene sequencing, network pharmacology analysis, molecular docking analysis, and molecular biological analyses were integrated to investigate the metabolic, microbial, and signaling changes associated with its therapeutic activity.

RESULTS: WWHLW exhibited anti-H. pylori activity, with minimum inhibitory concentrations (MICs) of 0.2-0.5 mg/mL against both standard strains and multidrug-resistant clinical isolates. At MIC concentrations, WWHLW treatment altered the expression of multiple virulence-associated genes and reduced gastric H. pylori colonization by 93.8% in infected mice. UHPLC-HRMS/MS analysis putatively annotated 121 compounds in the WWHLW extracts, of which 10 prototype constituents were detected in serum after oral administration. Integrated metabolomics and network pharmacology analyses revealed alterations in lipid and amino acid-related metabolic pathways following WWHLW treatment. Gut microbiota analysis showed that WWHLW was associated with less pronounced alterations in microbial diversity and composition than antibiotic treatment. Correlation analysis further revealed statistical associations between microbial taxa and lipid and amino acid-related features. Experimental validation showed that WWHLW reduced inflammatory cytokine expression and suppressed STAT3 phosphorylation, consistent with altered IL-6/STAT3-related molecular changes.

CONCLUSIONS: WWHLW exhibits therapeutic potential against H. pylori infection and HAG through combined antibacterial, anti-inflammatory and metabolic regulatory effects. The protective activity of WWHLW was associated with reduced IL-6/STAT3 signaling, providing pharmacological evidence supporting its traditional use in gastrointestinal disorders.

PMID:42700849 | DOI:10.1016/j.jep.2026.122370

Front Physiol. 2026 Aug 20;17:1930628. doi: 10.3389/fphys.2026.1930628. eCollection 2026.

ABSTRACT

BACKGROUND: Gastrointestinal motility disturbances rank among the most frequently reported medical complications of spaceflight. Astronauts experience delayed gastric emptying, erratic small intestinal transit and reduced colonic propulsion. The underlying mechanisms are multifactorial. Microgravity alters intra-abdominal physical mechanics, disrupts autonomic and enteric neural circuits, shifts gastrointestinal hormone secretion profiles, inflicts oxidative stress upon effector cells, and perturbs gut microbial communities. Cross-model comparisons reveal substantial disagreement, suggesting that no single ground-based analog fully captures the pathophysiology of orbital flight.

AIM: To critically review how weightlessness affects gastric emptying, small intestinal transit and colonic motility; to critically evaluate contradictory findings across simulation platforms; and to delineate the neural, humoral, cellular and microbiological mechanisms involved.

METHODS: We searched PubMed, Web of Science and the NASA Technical Reports Server for articles published between January 1990 and June 2026 (last search 30 June 2026). Search terms included: "microgravity", "weightlessness", "spaceflight", "gastrointestinal motility", "gastric emptying", "intestinal transit", "gut microbiome", "interstitial cells of Cajal" and "oxidative stress". Studies using head-down bed rest, hindlimb unloading, clinorotation, parabolic flight and actual spaceflight were included. The review follows a critical narrative design; the full search strategy and the framework used to appraise the evidence are described in Section 1.1.

RESULTS: Altered-gravity studies suggest that gastrointestinal dysmotility may involve neurohumoral dysregulation, oxidative injury to interstitial cells of Cajal and smooth muscle, barrier dysfunction and altered enteric signaling; however, most mechanistic evidence derives from simulated models and has not been directly validated during human spaceflight. Direct human motility measurements remain sparse, and the evidence comprises a mixture of direct observations, model-dependent inferences and testable hypotheses. Cross-study agreement is poor: some head-down bed rest trials report accelerated small-bowel transit, whereas tail-suspension models and limited flight observations suggest motor suppression. These divergences may reflect model-specific confounding rather than a uniform effect of microgravity.

CONCLUSION: Current ground-based models each capture only partial aspects of orbital GI pathophysiology. Future work should combine multi-omics profiling with next-generation simulation platforms to develop evidence-based countermeasures for long-duration missions.

PMID:42694486 | PMC:PMC13539599 | DOI:10.3389/fphys.2026.1930628

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

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

EPMA J. 2026 Aug 21;17(3):665-700. doi: 10.1007/s13167-026-00465-4. eCollection 2026 Sep.

ABSTRACT

Chronic atrophic gastritis (CAG) is a critical precancerous stage in the development of gastric cancer (GC). Circadian rhythm disruption perturbs the core clock gene network, including circadian locomotor output cycles kaput (CLOCK), brain and muscle ARNT-like 1 (BMAL1), period circadian protein homolog (PER), and cryptochrome (CRY). These alterations contribute to a multi-layered pathological cascade involving DNA damage accumulation, epigenetic remodeling, altered epithelial cell plasticity, cellular senescence, microbiota dysbiosis, tumor microenvironment remodeling, metabolic reprogramming, aberrant angiogenesis, and dysregulated cell death, thereby accelerating CAG to GC progression. However, existing studies have predominantly treated the circadian rhythm as a passive risk factor for disease onset and have yet to elevate it to an actionable interventional target within the full-course management of gastric precancerous lesions. Building on a systematic synthesis of the mechanistic evidence outlined above, this review proposes a predictive, preventive and personalised medicine (PPPM/3PM) three-tier management framework grounded in circadian-based individualised protection. At the predictive level, digital biomarkers (sleep-wake rhythms, light exposure, physical activity, and dietary behavior), multi-omics profiles, and circadian-related molecular signatures are integrated to achieve dynamic risk stratification of CAG populations. At the targeted prevention level, pharmacological agents and natural compounds with circadian-regulating potential are deployed to develop proactive protective strategies tailored to distinct pathological stages and circadian phenotypes. At the personalised treatment level, lifestyle interventions, chronotherapy, nano-carrier-based circadian-synchronised delivery, and dynamic biomarker monitoring are combined to formulate precision intervention regimens informed by individual circadian phenotypes. This framework repositions the circadian rhythm from a latent risk factor to a protectable and therapeutically targetable axis, offering new insights into time-optimised intervention strategies for the inflammation to cancer transition in CAG.

PMID:42682657 | PMC:PMC13530114 | DOI:10.1007/s13167-026-00465-4

Chem Biol Drug Des. 2026 Sep;108(3):e70386. doi: 10.1111/cbdd.70386.

ABSTRACT

Emerging evidence indicates that coagulation-related molecular programs are associated with thrombosis, tumor progression, and molecular dysregulation in gastric cancer (GC). However, thrombosis-associated molecular features in GC and their potential links to inherited susceptibility remain insufficiently understood. Integrated analyses of transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were performed to identify thrombosis-associated genes and establish a machine learning-based prognostic signature. Genome-wide association study (GWAS), expression quantitative trait loci (eQTL), transcriptome-wide association study (TWAS), and Mendelian randomization (MR) analyses were conducted to investigate susceptibility-associated transcriptional programs in GC. Functional assays were used to evaluate candidate genes associated with malignant phenotypes. Single-cell RNA sequencing (scRNA-seq) and cell-cell communication analyses were further performed to characterize cell-type-specific expression patterns and potential intercellular interactions. A total of 22 differentially expressed thrombosis-associated genes were identified, and a prognostic signature comprising 14 genes was established. The signature stratified patients into high- and low-risk groups and showed prognostic performance in both the training and validation cohorts. Integrative GWAS, eQTL, and TWAS analyses identified susceptibility-associated transcriptional programs that were positively correlated with the thrombosis-associated risk score. Silencing ACTN2 and CRYAB significantly reduced GC cell migration and invasion. scRNA-seq analysis revealed relatively high CRYAB expression in neutrophils, and CellChat analysis suggested potential neutrophil-B cell interactions involving COLLAGEN-related signaling. This integrative multi-omics study identified a thrombosis-associated molecular signature linked to prognosis and germline susceptibility-associated transcriptional programs in GC. ACTN2 and CRYAB may represent candidate genes associated with GC cell migration and invasion, while single-cell analysis suggested potential immune-related communication features.

PMID:42681916 | PMC:PMC13534880 | DOI:10.1111/cbdd.70386

Cell Cycle. 2026 Dec;25(1):1-29. doi: 10.1080/15384101.2026.2725418. Epub 2026 Sep 1.

ABSTRACT

Gastrointestinal (GI) cancers, including colorectal, gastric, pancreatic, hepatocellular, and esophageal malignancies, remain a leading cause of cancer-related mortality worldwide. Emerging evidence identifies the gut microbiome as a critical regulator of GI carcinogenesis, influencing tumor initiation, immune evasion, therapeutic response, and clinical outcomes through inflammation, genotoxicity, metabolic reprogramming, and epithelial barrier disruption. Importantly, biological rationale, clinical evidence, and translational opportunities differ across GI tumor types. Specific taxa, including Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, pks⁺ Escherichia coli, and Helicobacter pylori, exhibit tumor-specific oncogenic roles with causal evidence ranging from associative to guideline-validated. Microbiome-based biomarkers, including composite multi-taxon models and signatures predictive of immune checkpoint inhibitor response, are evaluated using a four-tier framework (preclinical, associative, near-clinical, and validated). Microbiome-targeted therapies, including probiotics, fecal microbiota transplantation, dietary modulation, and engineered microbial therapeutics, are critically appraised according to clinical evidence and translational readiness. Advances in spatial microbiomics, single-cell analysis, multi-omics, and artificial intelligence may further accelerate microbiome-based precision oncology. This review provides a translationally stratified synthesis of microbiome-GI cancer interactions and their implications for precision oncology.

PMID:42677508 | PMC:PMC13540093 | DOI:10.1080/15384101.2026.2725418

Clin Transl Med. 2026 Sep;16(9):e70784. doi: 10.1002/ctm2.70784.

ABSTRACT

BACKGROUND: As a pivotal metabolic enzyme, cysteine dioxygenase type 1 (CDO1) exerts tumour-suppressive effects across diverse tumour types, and its expression is strongly correlated with clinical prognosis. However, the molecular mechanisms underlying CDO1-mediated tumour suppression in gastric cancer (GC), its relationship with the tumour-associated immune microenvironment, and pharmacological strategies to restore its expression remain poorly understood.

METHODS: CDO1 expression and prognosis were evaluated by multi-omics and tissue microarray analyses. Tumour microenvironment and immune infiltration were analyzed using ESTIMATE and ssGSEA. Downstream pathways and interacting proteins were identified by transcriptomics, co-immunoprecipitation, and GST pull-down. CDO1 function was assessed by proliferation, apoptosis, and migration assays in gain- and loss-of-function models. In vivo tumorigenesis and CDO1-dependent decitabine efficacy were evaluated by subcutaneous xenografts. Patient-derived organoids were used to assess decitabine sensitivity and 5-FU synergy.

RESULTS: Compared with normal controls, CDO1 expression was notably decreased in GC tissues, and its low expression was strongly linked to unfavourable prognosis, supporting its utility as a biomarker for prognosis. Elevated CDO1 levels correlated with an immune-active tumour microenvironment and reduced metastatic signatures. Mechanistically, CDO1 directly bound to PI3K p85α, disrupting p85α-p110α dimerization, thereby attenuating PI3K/AKT phosphorylation and downregulating THBS1 expression. CDO1 overexpression led to reduced proliferation, invasiveness, and EMT, accompanied by increased apoptosis. These effects were reversed by PI3K activation or THBS1 co-overexpression. Decitabine was identified as an agent that epigenetically restores CDO1 expression. Critically, CDO1 knockdown significantly attenuated the anti-tumour efficacy of decitabine in vivo, confirming that decitabine acts primarily through CDO1 reactivation. Decitabine synergized with 5-FU in both organoids and xenografts.

CONCLUSIONS: Our data identify CDO1 as both a biomarker for prognosis and a tumour suppressor in gastric cancer. They reveal a CDO1-PI3K/AKT-THBS1 signalling axis and support the epigenetic reactivation of CDO1 by decitabine as a translatable therapeutic strategy.

KEY POINTS: CDO1 is frequently downregulated in gastric cancer and serves as an independent favourable prognostic biomarker. CDO1 directly binds PI3K p85α, disrupting p85α-p110α dimerization to suppress the PI3K/AKT-THBS1 signalling axis. Decitabine epigenetically restores CDO1 expression, and its anti-tumour activity is critically CDO1-dependent in vivo. Combining decitabine with 5-FU synergistically overcomes gastric cancer growth in patient-derived organoids and subcutaneous xenograft models.

PMID:42670236 | PMC:PMC13527532 | DOI:10.1002/ctm2.70784

J Ethnopharmacol. 2026 Aug 29;373:122318. doi: 10.1016/j.jep.2026.122318. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Helicobacter pylori (H. pylori) infection is a leading risk factor for chronic gastritis, peptic ulcers, and gastric cancer. The escalating antibiotic resistance of H. pylori and adverse effects arising from standard antibiotic regimens have underscored an urgent need for natural, food-complementary therapeutic alternatives. Terminalia chebula Retz., commonly named "Hezi" in traditional Chinese medicine and "Haritaki" in Ayurveda, is a well-recognized edible fruit with a long history of use in alleviating gastrointestinal disorders.

AIM OF THE STUDY: While it has been traditionally recognized for its anti-inflammatory and antimicrobial properties, its anti-adhesive efficacy against H. pylori and the metabolic mechanisms underlying its in vivo effects remain largely unexplored.

MATERIALS AND METHODS: This study adopted multiple analytical and experimental approaches: ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), RNA-seq, cell viability and adhesion assays, western blotting, hematoxylin and eosin (H&E) staining, enzyme-linked immunosorbent assay (ELISA), metabolomics, and proteomics.

RESULTS: In this study, 15 primary compounds in T. chebula aqueous extract were identified, predominantly tannins. Multi-omics analyses (transcriptomics, metabolomics, and proteomics) revealed that T. chebula aqueous extract significantly inhibited H. pylori adhesion and enriched the lysine degradation pathway. Notably, N-alpha-acetyl-L-lysine was characterized as a key metabolite in fecal metabolomic profiling, which was associated with glycosphingolipid biosynthesis, ferroptosis, HIF-1 signaling, lysosomal function, and arginine metabolism. In vitro assays confirmed that N-alpha-acetyl-L-lysine reduced H. pylori adhesion to GES-1 cells, reversed H. pylori-induced cellular damage, and suppressed the secretion of pro-inflammatory cytokines (IL-6 and TNF-α). In vivo, T. chebula aqueous extract administration markedly alleviated H. pylori-induced gastric inflammation by downregulating IL-6, IL-1β, TNF-α, TGF-β, and IFN-γ. Collectively, these findings demonstrate that T. chebula aqueous extract exerts anti-H. pylori effects by regulating lysine metabolism, with N-alpha-acetyl-L-lysine serving as a key metabolite via fecal metabolomics.

CONCLUSION: These findings highlight T. chebula's promising potential as a functional food ingredient or adjunctive therapy for H. pylori-related diseases, providing a natural, mechanism-based option for clinical intervention.

PMID:42665167 | DOI:10.1016/j.jep.2026.122318

Int J Antimicrob Agents. 2026 Aug 28:107981. doi: 10.1016/j.ijantimicag.2026.107981. Online ahead of print.

ABSTRACT

Antibiotic resistance in Helicobacter pylori is an important factor in the ineffectiveness of eradication regimens. The rate of resistance is not constant and varies widely by region and over time. Resistance is mainly due to point mutations in target genes like 23S rRNA (clarithromycin), gyrA/gyrB (fluoroquinolones), rdxA/frxA (metronidazole), and PBP1 (amoxicillin). Moreover, multi-drug resistance is mediated by efflux proteins (e.g., HefA, RND proteins), biofilm formation, and phase-variable epigenetics like DNA methylation, which regulate virulence and stress response. Immune evasion by the bacterium involves Toll-like receptor modulation, cytokine (IL-1β, TNF-α, IL-8) dysregulation, miRNA (e.g., miR-146, miR-155) modification, and persistent epigenetic field defects post-eradication, which may result in carcinogenesis via NF-κB and STAT3 signaling. H. pylori also induces gastric microbiome dysbiosis, with reduced microbial diversity, increased pro-inflammatory species, and extragastric manifestations like iron deficiency anemia, metabolic syndrome, and neurological complications. Microbiome-directed therapies, such as probiotics (Lactobacillus, Bifidobacterium), have been demonstrated to increase eradication success to 78-88%. Machine learning algorithms, including XGBoost and CNNs, accurately predict resistance from genomic sequences with over 90% sensitivity, integrating multi-omics for personalized therapy. Efflux pumps are key in multidrug resistance, while host epigenetics plays a role in bacterial persistence. Approaches include susceptibility testing, bismuth quadruple therapy, and novel adjuncts such as fecal microbiota transplantation. Prompt and personalized eradication is essential in overcoming antimicrobial resistance and preventing oncogenic transformation.

PMID:42665067 | DOI:10.1016/j.ijantimicag.2026.107981

Front Mol Biosci. 2026 Aug 12;13:1752442. doi: 10.3389/fmolb.2026.1752442. eCollection 2026.

ABSTRACT

BACKGROUND: While MUC family genes have been established as prognostic biomarkers in gastric cancer, and GWAS studies link EMCN mutations to chemotherapy-induced myelosuppression in NSCLC, the systematic characterization of EMCN in lung adenocarcinoma (LUAD) remains elusive.

METHODS: This multi-omics strategy combining bulk and single-cell transcriptomics study integrated differential expression analysis, WGCNA, and machine learning algorithms (LASSO/SVM-RFE/Random Forest) to identify EMCN as a diagnostic hub gene, followed by experimental validation using immunohistochemistry Western blot and qRT-PCR.

RESULTS: EMCN (Endomucin) is a sialomucin-like glycoprotein predominantly expressed in vascular endothelial cells. Using bulk transcriptomic datasets and single-cell RNA-seq analysis, we found that EMCN expression was reduced in lung adenocarcinoma (LUAD) compared with non-tumor controls and was primarily localized to the endothelial compartment. Survival analysis using the median expression cutoff showed that high EMCN expression was associated with improved overall survival (Cox HR_high vs. low = 0.73, p = 0.04), indicating that low EMCN expression correlates with poorer prognosis. Machine learning-based feature selection (LASSO, Random Forest, and SVM) further prioritized EMCN among consensus candidate genes, supporting its potential relevance to the vascular-associated tumor microenvironment in LUAD. EMCN expression levels also showed a significant positive correlation with the degree of immune cell infiltration. Gene set enrichment analysis (GSEA) revealed that high EMCN expression in tumor tissues activates negative regulatory pathways associated with angiogenesis. Receiver operating characteristic (ROC) curve analysis highlights EMCN's excellent diagnostic potential for LUAD, with an area under the curve (AUC) of 0.963. In vitro experiments confirm the downregulation of EMCN at both protein and mRNA levels, consistent with our bioinformatics predictions.

CONCLUSION: This first comprehensive study establishes EMCN as a dual-functional regulator of vascular-immune crosstalk in LUAD, providing both a molecular diagnostic tool and therapeutic target for precision oncology.

PMID:42656419 | PMC:PMC13506425 | DOI:10.3389/fmolb.2026.1752442

Vet Sci. 2026 Aug 18;13(8):823. doi: 10.3390/vetsci13080823.

ABSTRACT

The equine gastrointestinal microbiome plays an essential role in digestion, energy metabolism, immune regulation, and maintenance of intestinal homeostasis. Increasing evidence suggests that microbial-derived metabolites provide a functional link between diet, the microbiome, and host physiology. This narrative review summarizes current knowledge on how dietary factors, including structural carbohydrates, non-structural carbohydrates, protein, and lipids, influence microbial function and metabolite production in horses. Relevant publications available up to June 2026 were identified through searches of PubMed, Web of Science, Scopus, and Google Scholar and were narratively synthesized according to dietary factors, microbial metabolites, associated diseases, and nutritional interventions. Emphasis is placed on major microbial metabolites, including short-chain fatty acids, endotoxins, bile acid derivatives, tryptophan metabolites, and nitrogenous fermentation products, and their potential roles in health and disease. Current evidence supports a central role for the nutrition-microbiota-metabolite axis in gastrointestinal disorders such as colic, colitis, equine gastric ulcer syndrome, and carbohydrate-associated laminitis, whereas its involvement in equine metabolic syndrome and the gut-lung axis remains less well defined. The review also discusses microbiome-targeted nutritional interventions and emerging multi-omics approaches that are improving our understanding of microbial function. Collectively, these findings highlight the potential of microbiome-informed nutritional strategies to support equine health, welfare, disease prevention, and athletic performance.

PMID:42655843 | PMC:PMC13517798 | DOI:10.3390/vetsci13080823

Front Immunol. 2026 May 8;17:1742982. doi: 10.3389/fimmu.2026.1742982. eCollection 2026.

ABSTRACT

BACKGROUND: Filaggrin (FLG) plays an important role in the progression of malignant tumors; however, its expression characteristics and biological functions in gastric cancer (GC) remain unclear.

METHODS: Cancer-related datasets were retrieved from public repositories, including the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). A competing endogenous RNA (ceRNA) network was constructed to explore potential regulatory networks involving FLG. Differential expression analysis, genetic alteration analysis, and clinicopathological and survival analyses were performed to evaluate the role of FLG in GC. In addition, Gene Set Enrichment Analysis (GSEA), immune infiltration analysis, and in vitro functional experiments were conducted to investigate the biological effects and potential mechanisms of FLG in GC.

RESULTS: FLG was aberrantly expressed across multiple cancer types and was significantly associated with clinical characteristics and prognosis in GC. Further analyses showed that FLG was involved in genetic alterations and was closely associated with the immune microenvironment in GC. Functional experiments demonstrated that FLG promoted the invasion and metastasis of GC cells. Mechanistically, GSEA and experimental validation indicated that FLG exerted its tumor-promoting effects, at least in part, through activation of the epithelial-mesenchymal transition (EMT) signaling pathway.

CONCLUSION: This study clarifies the biological role of FLG in GC and highlights its potential as a novel prognostic biomarker and therapeutic target. These findings provide new insights into the molecular mechanisms underlying GC progression and may contribute to the development of more effective diagnostic and therapeutic strategies.

PMID:42183248 | PMC:PMC13194527 | DOI:10.3389/fimmu.2026.1742982

Curr Oncol Rep. 2026 May 22;28(1):58. doi: 10.1007/s11912-026-01793-4.

ABSTRACT

PURPOSE OF REVIEW: To provide an updated overview of the role of the human microbiome in the initiation, progression, and therapeutic response of gastrointestinal tumors, emphasizing molecular, immunological, and metabolic mechanisms, as well as its potential as a target for novel therapeutic strategies.

RECENT FINDINGS: Emerging evidence demonstrates that microbiome dysbiosis contributes to carcinogenesis across gastrointestinal malignancies, including colorectal, gastric, hepatic, and pancreatic cancers. Microbial-derived metabolites, such as short-chain fatty acids and secondary bile acids, modulate key signaling pathways involved in cell proliferation, apoptosis, and genomic stability. In addition, the microbiome influences the tumor microenvironment and immune responses, shaping variability in treatment outcomes. Both preclinical and clinical studies have shown that microbiome composition affects the efficacy and toxicity of chemotherapy and immunotherapy. Notably, specific microbial signatures are being explored as non-invasive biomarkers for early detection and prognostic stratification, while microbiome modulation strategies, such as diet, probiotics, antibiotics, and fecal microbiota transplantation, have demonstrated potential to enhance therapeutic response. The bidirectional interaction between the microbiome and the host plays a central role in gastrointestinal tumorigenesis and treatment response. Although this field holds significant promise for precision oncology, its clinical translation remains limited by interindividual variability, methodological heterogeneity, and insufficient longitudinal evidence. Future efforts should focus on standardization, validation of microbiome-based biomarkers, and integration of multi-omics and artificial intelligence approaches to enable clinically actionable applications.

PMID:42171841 | DOI:10.1007/s11912-026-01793-4

Front Cell Dev Biol. 2026 May 1;14:1807136. doi: 10.3389/fcell.2026.1807136. eCollection 2026.

ABSTRACT

BACKGROUND: Therapeutic vulnerability in gastric cancer is profoundly influenced by the tumor microenvironment (TME), yet reliable and clinically actionable preoperative indicators remain insufficient.

METHODS: We developed and validated an artificial intelligence-driven multi-omics TME score (DLRS/TMEscore) by integrating CT-derived imaging features with transcriptomic, immunohistochemical, and molecular profiling. The score was evaluated for its associations with survival outcomes, benefit from adjuvant chemotherapy, and response to anti-PD-1 therapy.

RESULTS: The DLRS/TMEscore reproducibly stratified disease-free and overall survival across independent cohorts. Patients in the low-risk subgroup derived substantial benefit from adjuvant chemotherapy, whereas those in the high-risk subgroup demonstrated attenuated benefit. Among individuals receiving immunotherapy, the score enriched objective responders and predicted more durable clinical outcomes, outperforming established biomarkers including PD-L1 combined positive score (CPS) and microsatellite instability (MSI). In addition, DLRS/TMEscore correlated with multiple surgical parameters, such as operative complexity, resection margin status, nodal involvement, and postoperative recovery, indicating relevance in perioperative risk assessment.

CONCLUSION: This AI-enabled multi-omics framework offers a robust and interpretable approach for characterizing microenvironment-defined therapeutic vulnerability, supporting preoperative risk stratification and individualized systemic treatment strategies in gastric cancer.

PMID:42148312 | PMC:PMC13176314 | DOI:10.3389/fcell.2026.1807136

Chin J Cancer Res. 2026 Apr 30;38(2):234-251. doi: 10.21147/j.issn.1000-9604.2026.02.09.

ABSTRACT

OBJECTIVE: Gastric cancer (GC) is heterogeneous, and current mismatch repair (MMR)-based classifications incompletely predict response to immune checkpoint inhibitors (ICIs).

METHODS: RNA sequencing (RNA-seq) and immune infiltration profiles from 189 resected GC were used to derive four refined immune-MMR subtypes (R1-R4) by integrating MMR status, survival, and tumor microenvironment (TME) features. Multi-omics profiling and pathway analysis defined subtype biology. External transcriptomic cohorts and an ICI-treated cohort were classified with Nearest Template Prediction (NTP). Immune response-associated genes were identified from responder vs. non-responder comparisons within the ICI-sensitive subtype and validated by multiplex immunohistochemistry (mIHC).

RESULTS: R1 showed the best prognosis and highest immunotherapy response with objective response rate (ORR) 54.5%, while R4 had the worst prognosis. R2 represented an immune-unresponsive deficient mismatch repair (dMMR) subset, and R3 captured an immune-active proficient mismatch repair (pMMR) subgroup with moderate therapy sensitivity. Multi-omics integration revealed subtype-specific pathways (e.g., ECM remodeling in R1, metabolic reprogramming in R2). Reclassification of pMMR tumors based on transcriptional similarity to R1 identified a New R3 subset with enhanced immune features and higher ICI response. Eight immune response-associated genes (e.g., CXCL10, CXCL11, ELN, GAD1, IL32, MT1E, OR2I1P, SLC3A1) were identified and validated by mIHC for predictive relevance.

CONCLUSIONS: This immune-based molecular framework refines risk stratification beyond conventional MMR categories, identifies ICI-sensitive subsets among both dMMR and pMMR tumors, and proposes candidate biomarkers for patient selection.

PMID:42147371 | PMC:PMC13171420 | DOI:10.21147/j.issn.1000-9604.2026.02.09

Front Oncol. 2026 May 1;16:1785100. doi: 10.3389/fonc.2026.1785100. eCollection 2026.

ABSTRACT

BACKGROUND: Acquired resistance to cisplatin-based chemotherapy is common in patients with gastric cancer (GC) and significantly limits treatment efficacy. The aim of this study was to investigate molecular features associated with GC chemoresistance using an integrative multi-level analytical framework combined with Mendelian randomization (MR), followed by cellular validation of key candidates.

METHODS: Transcriptome datasets GSE14210 and GSE31811 were obtained from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to explore potential pathways. A total of 113 machine learning model combinations were applied for feature selection. MR analysis integrating expression quantitative trait loci (eQTLs) and genome-wide association study (GWAS) data was conducted to assess causal relationships between candidate genes and chemoresistance. The single-cell dataset GSE183904 was used to examine cell-type-specific expression patterns. Cisplatin-resistant NCI-N87/DDP cells were then established in vitro, and qRT-PCR, Western blotting, and drug sensitivity assays were performed to evaluate gene expression and function. Pathway inhibitors were applied to test the reversal of resistance.

RESULTS: A total of 827 DEGs were identified, mainly enriched in immune response, ECM interactions, metabolic reprogramming, and signaling pathways such as PI3K-Akt and MAPK. Among the machine learning models, the Stepglm[both] + Random Forest (RF) model achieved the best performance [area under the curve (AUC) = 0.865] and identified several core candidate genes. MR analysis supported potential risk associations for TRABD, RXRA, DEFA4, PARP16, SLC12A9, and TMEM132A, with PARP16 consistently highlighted across transcriptomic, machine learning, and MR analyses. In vitro experiments showed that PARP16 expression was elevated by approximately 3.1-fold in NCI-N87/DDP cells, accompanied by activation of the unfolded protein response (UPR) and suppression of apoptosis, and an elevated cisplatin IC₅₀ of 11.82 μg/mL. Inhibition of the PARP16-UPR axis significantly reduced the IC₅₀ to 4.67 μg/mL and restored DNA damage and apoptosis, demonstrating synergistic effects.

CONCLUSIONS: PARP16 emerged as a key candidate associated with chemoresistance in GC. Its elevated expression in stem-like cell populations and resistant cell models was associated with UPR activation, and targeting the PARP16-UPR axis restored cisplatin sensitivity. Targeting the PARP16-UPR axis effectively reverses resistance, providing new insights and potential therapeutic strategies for overcoming chemoresistance in GC.

PMID:42147232 | PMC:PMC13175845 | DOI:10.3389/fonc.2026.1785100