World J Surg Oncol. 2026 Apr 7. doi: 10.1186/s12957-026-04321-7. Online ahead of print.

NO ABSTRACT

PMID:41947143 | DOI:10.1186/s12957-026-04321-7

J Gastric Cancer. 2026 Apr;26(2):260-278. doi: 10.5230/jgc.2026.26.e19.

ABSTRACT

PURPOSE: Patient-derived cells (PDCs) and patient-derived organoids (PDOs) are complementary preclinical models widely used in translational cancer research. However, their molecular and functional differences have not been systematically characterized. This study established and analyzed paired PDC and PDO models derived from the same gastric cancer ascites to delineate platform-dependent molecular and functional profiles.

MATERIALS AND METHODS: Malignant ascites or pleural fluid obtained from 6 patients with advanced gastric cancer were used to establish paired PDC and PDO models. All pairs underwent comprehensive multi-omics profiling, integrating genomic, transcriptomic, and proteomic data. Phenotypic characterization included morphological, histological, proliferative, and cell cycle analyses. Drug sensitivity assays were performed using 4 chemotherapeutic agents commonly used to treat gastric cancer.

RESULTS: The 6 paired PDC and PDO models exhibited distinct morphological characteristics. Whole-genome analyses demonstrated high concordance among primary tumors, PDCs, and PDOs, confirming tumor representation across platforms. Multi-omics profiling identified platform-dependent molecular signatures; PDOs were enriched for extracellular matrix remodeling and stemness, whereas PDCs displayed proliferation- and immune-related signatures. Clinically relevant biomarkers, including HER2 and MET alterations, were concordant with primary tumors. Notably, drug responses differed between platforms and patients, indicating platform-dependent and patient-specific chemosensitivity.

CONCLUSIONS: Paired PDC and PDO models derived from the same patients preserved core patient-specific tumor characteristics while exhibiting distinct molecular and functional profiles. These findings underscore the culture platform as a critical determinant of experimental outcomes and therapeutic responses. Therefore, careful selection of an appropriate preclinical model is essential to accurately address biological questions and optimize precision oncology strategies.

PMID:41942359 | PMC:PMC13053824 | DOI:10.5230/jgc.2026.26.e19

Phytomedicine. 2026 Mar 27;155:158126. doi: 10.1016/j.phymed.2026.158126. Online ahead of print.

ABSTRACT

BACKGROUND: Mitochondrial damage can induce the release of mitochondrial DNA (mtDNA), leading to oxidative stress and activation of immune responses. Targeting mitochondrial dysfunction may thus represent a therapeutic strategy for gastric cancer. Isobavachalcone (IBC), a prenylated chalcone derived from Psoralea corylifolia L., has demonstrated antitumor activity, but its mechanism of action remains unclear, limiting its clinical application.

PURPOSE: This study aimed to investigate the antitumor effects of IBC in gastric cancer and to elucidate the underlying molecular mechanisms, with a focus on mitochondrial damage and immune activation.

STUDY DESIGN: The study combined in vitro and in vivo assays with multi-omics sequencing and network pharmacology to identify IBC's therapeutic target and downstream signaling pathways.

METHODS: Gastric cancer cells and mouse models were treated with IBC to assess its inhibitory effects. Multi-omics approaches and network pharmacology were used to identify potential targets. ROS production, mitochondrial membrane integrity, and immune pathway activation were evaluated via biochemical and molecular assays.

RESULTS: IBC significantly suppresses gastric cancer growth both in vitro and in vivo. Integrated analysis identifies dihydroorotate dehydrogenase (DHODH) as a direct target of IBC. DHODH deficiency can induce mitochondrial membrane remodeling and STING pathway activation. Inhibition of DHODH by IBC induces ROS accumulation, mitochondrial membrane remodeling, and activation of the STING pathway, promoting antitumor immune responses. This study demonstrates that IBC enhances antitumor immunity in gastric cancer through mitochondrial damage-mediated mechanisms.

CONCLUSION: IBC exerts dual antitumor and immunostimulatory effects in gastric cancer by targeting DHODH, inducing mitochondrial damage, and activating the STING pathway, highlighting its promising therapeutic potential in gastric cancer.

PMID:41931998 | DOI:10.1016/j.phymed.2026.158126

PLoS One. 2026 Apr 3;21(4):e0346173. doi: 10.1371/journal.pone.0346173. eCollection 2026.

ABSTRACT

Cancer remains a leading cause of mortality worldwide and a significant barrier to improving quality of life across all populations. The protein kinase D family, including PRKD3, has been demonstrated to play a crucial role in cancer development through its involvement in regulating key cellular processes. Although growing evidence highlights the role of PRKD3 in the tumorigenesis of certain cancers, a comprehensive pan-cancer analysis of PRKD3 remains unavailable. To address this, we performed an integrative pan-cancer analysis of PRKD3 using multi-omics datasets from The Cancer Genome Atlas, the Genotype-Tissue Expression project, and cBioPortal. We examined PRKD3 expression, copy number variation, mutation, and DNA methylation, and evaluated their associations with clinicopathological features, patient survival, and diagnostic potential across 33 cancer types. Immune relevance was further assessed through correlations with immune infiltration, checkpoint gene expression, and immunotherapy response-related genomic biomarkers. Our results revealed that PRKD3 expression was highly heterogeneous, showing significant upregulation in liver cancer, gastric cancer, and adrenocortical carcinoma, and downregulation in others. Elevated expression was consistently associated with poor prognosis and increased stromal, neutrophil, and cancer-associated fibroblast infiltration in adrenocortical carcinoma, liver cancer, and stomach cancer, whereas paradoxical associations with favorable outcomes were observed in kidney clear cell carcinoma. PRKD3 expression also correlated with immune checkpoint molecules including PD-1, PD-L1, and CTLA-4, supporting an immunosuppressive role, while context-dependent associations with TMB and MSI highlighted its potential influence on tumor immunogenicity and responsiveness to immune checkpoint blockade. Collectively, these findings identify PRKD3 as a potential context-dependent modulator of tumor biology, prognosis, and immune interactions, underscoring its potential as a biomarker of diagnostic, prognostic, and therapeutic relevance in precision oncology.

PMID:41931575 | PMC:PMC13048501 | DOI:10.1371/journal.pone.0346173

Eur J Cancer. 2026 Mar 24;239:116699. doi: 10.1016/j.ejca.2026.116699. Online ahead of print.

ABSTRACT

INTRODUCTION: The latest generation of liquid biopsies incorporates multi-omic features, including genomics, methylomics, and fragmentomics. Machine learning (ML) approaches have been proposed to synthesize these complex biological data for the development of diagnostic classifiers. This study aims to evaluate the integration of ML with circulating cell-free DNA (cfDNA) analysis for early cancer detection.

METHODS: Medline, Embase, Cochrane, and Web of Science were searched in July 2025. Eligible studies combined ML and cfDNA features to distinguish cancer patients (stages I-III) from non-cancer controls. Summary diagnostic performance metrics and their 95% confidence intervals (CI) were calculated.

RESULTS: The study included 109 articles permitting analyses for lung (n = 34), liver (n = 29), colorectal (n = 28), pancreatic (n = 16), breast (n = 17), esophageal (n = 12), ovarian (n = 13), gastric (n = 9), head and neck (n = 4), and mixed (n = 27) cancer types. Specificity was consistently high across all tumor types and stages (94%-99%). Sensitivity ranged from 72% to 92% for stage I-III, 44-91% for stage I, 71-98% for stage II and 83-99% for stage III. In the pooled study population, neural networks (90%, 95% CI: 81%-95%), random forest (86%, 95% CI: 77%-92%) and heterogeneous ensemble learning (85%, 95% CI: 79%-89%) demonstrated the highest sensitivity. The stratified analysis by classifier feature revealed 86% (95% CI: 80%-90%) sensitivity for fragmentation and 81% (95% CI: 76%-85%) for methylation, with 92%-96% specificity.

CONCLUSION: ML and cfDNA profiling show potential for early cancer detection, with ensemble methods, neural networks and random forests achieving the best overall performance. Fragmentomic features provide the highest sensitivity.

PMID:41930854 | DOI:10.1016/j.ejca.2026.116699

Arterioscler Thromb Vasc Biol. 2026 Apr 2. doi: 10.1161/ATVBAHA.125.324171. Online ahead of print.

ABSTRACT

BACKGROUND: Joint use of multiple molecular layers can be useful to prioritize targets for mechanistic studies. Application of coronary disease in large populations is an emerging field.

METHODS: We used reported circulating proteomic data (Somascan aptamer-based) from ≈3000 individuals in the CARDIA study (Coronary Artery Risk Development in Young Adults), measuring association with prevalent and 10-year incident coronary artery calcium (CAC) score. We used a multiparametric approach to prioritize circulating protein-CAC associations via genomics of circulating protein levels and coronary artery transcription.

RESULTS: Proteins linked to prevalent/incident CAC in CARDIA implicated pathogenic mechanisms of vascular disease, including fibrosis and inflammation (GDF-15 [growth/differentiation factor 15], CDCP1 [CUB domain-containing protein 1], GSN [gelsolin], THBS2 [thrombospondin-2], chemokines, RNAS6), oxidative lipid metabolism (CILP2), extracellular matrix remodeling and signaling (MMPs [matrix metalloproteinases], TIMP-1, integrins), calcification (Notch 1, ARHGAP36 [Rho GTPase-activating protein 36]), and metabolism (GIP [gastric inhibitory polypeptide]), as well as new proteins not previously reported. Using protein-wide association study genetic approaches, several targets with nominal evidence in CAC proteomics were associated with atherosclerosis or myocardial infarction in over 300K individuals, including PCSK9 (proprotein convertase subtilisin/kexin type 9) and APO C₁. Finally, the coronary artery-specific transcriptome-wide association study of CAC yielded genes with previously implicated mechanistic roles in vascular homeostasis, inflammation, and metabolism, as well as genes without previously described function in CAC. Overlap across CAC proteomics and transcriptome-wide association study highlighted genes involved in vascular inflammation (S100A9), cardiac development (HES1), vessel wall structure (SPARCL1), and vascular dysfunction or plaque (NOTCH3, TNFSF12, S100A12).

CONCLUSIONS: These results report population-level multiomics in human coronary calcification, presenting a method to identify disease-relevant targets through integration of human genetic approaches with multiomics.

PMID:41924874 | DOI:10.1161/ATVBAHA.125.324171

Cancer Treat Rev. 2026 Apr;145:103124. doi: 10.1016/j.ctrv.2026.103124. Epub 2026 Mar 26.

ABSTRACT

Gastric and gastroesophageal junction adenocarcinoma (GC) is a biologically challenging malignancy associated with suboptimal clinical outcomes due to limited effective treatment options. The recent incorporation of immune checkpoint inhibitors (ICIs) into therapeutic algorithms has improved the clinical prospects of subsets of GC patients. However, responses to anti-PD-1/PD-L1 agents remain highly heterogeneous, with only some patients deriving long-term benefits. This variability highlights the importance of identifying optimal biomarkers to enhance patient selection, thereby enabling tailored immunotherapy strategies. Whereas microsatellite instability has demonstrated a potent capacity for predicting immunotherapy benefits in GC, other predictive biomarkers, such as PD-L1 expression, remain suboptimal. Advances in gene expression and epigenetic profiling, liquid biopsy approaches, gut microbiome characterization, and artificial intelligence-driven multimodal algorithms applied to multi-omics or digital pathology are key drivers for the comprehensive characterization of the GC tumour microenvironment (TME), which could be used for better treatment selection. Similarly, elucidating the complex tumour-immune interplay with these technologies will be crucial for the success of novel immunotherapeutic approaches under clinical development, by evaluating alternative immune pathways alone or in combination with current actionable targets of GC. The current review aims to give an overview of the current immunotherapeutic landscape in GC, evaluate standard-of-care and emerging biomarkers of immunotherapy response, and discuss the translational potential of incorporating multi-omic and AI-derived biomarkers into biomarker-enriched clinical decision-making frameworks.

PMID:41921305 | DOI:10.1016/j.ctrv.2026.103124

NPJ Precis Oncol. 2026 Mar 31. doi: 10.1038/s41698-026-01394-1. Online ahead of print.

ABSTRACT

VDAC2's known role in cancer and immune regulation via enhancing the CD8⁺ T cell-mediated killing, and it is worth systematically digging out the role of VDAC2 in pan-cancer based on this research. Bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomic analyses were utilized to explore the role of VDAC2 from multiple perspectives in pan-cancers. RT-PCR, cell co-culture, CCK-8 assay, Transwell invasion assays, and ELISA were performed to validate the expression level and biological function. VDAC2 was upregulated in the majority of pan-cancers, and functional enrichment analyses displayed that VDAC2 may take part in the biological progress of energy metabolism, mitochondrial damage and cell proliferation. The landscape of VDAC2 expression and immune infiltration was constructed, and the VDAC2-BAK1-IFNγ pathway was identified in digestive cancer. VDAC2 had the potential to serve as a novel prognostic, screening cancer indicator and immune therapeutic target sensitive to various drugs. Overexpression of VDAC2 significantly promoted gastric cancer cell proliferation, invasion and immune invasion, as validated in vitro experiments. In short, our pan-cancer analysis constructed a comprehensive landscape of VDAC2's oncogenic role, establishing VDAC2 + -BAK1-IFNγ as an important pathway in tumor progression and immune evasion. VDAC2 emerges not only as a valuable prognostic biomarker but also as a promising novel therapeutic target.

PMID:41917254 | DOI:10.1038/s41698-026-01394-1

Food Funct. 2026 Mar 31. doi: 10.1039/d5fo04958j. Online ahead of print.

ABSTRACT

The probiotic yeast Saccharomyces boulardii is renowned for its clinical efficacy, which is intrinsically linked to its exceptional ability to survive the harsh gastrointestinal (GI) environment. However, a comprehensive understanding of the molecular mechanisms and regulatory pathways underlying the stress tolerance of S. boulardii remains limited. This study employed an integrated transcriptomic and proteomic approach to systematically map the dynamic responses of S. boulardii to simulated GI transit. Our analysis revealed that the intestinal phase posed a significantly greater challenge than the gastric phase, triggering extensive molecular reprogramming. A core adaptive strategy was the marked upregulation of the central carbon metabolism, particularly glycolysis, as evidenced by the concerted overexpression of key enzymes at both transcriptional and translational levels, indicating a heightened demand for energy to fuel stress defence mechanisms. Furthermore, significant enrichment was observed in the pathways related to nitrogen and fatty acid metabolism. Integration of the multi-omics datasets highlighted the complexity of the regulatory response, with frequent discordance between mRNA and protein abundance underscoring the importance of post-transcriptional regulation. This study provides a detailed molecular profile of the stress tolerance network in S. boulardii, elucidating the strategic metabolic rewiring and multi-layered regulation that underpin its probiotic resilience. The findings offer valuable insights and a foundational resource for the future development of enhanced probiotic therapies.

PMID:41914832 | DOI:10.1039/d5fo04958j

Aging Dis. 2026 Mar 19. doi: 10.14336/AD.2025.1571. Online ahead of print.

ABSTRACT

Gastric cancer (GC) remains a leading cause of cancer-related morbidity and mortality worldwide, with poor prognosis for advanced-stage patients. Therefore, in-depth exploration of the mechanisms underlying GC initiation and progression, as well as the development of novel therapeutic strategies, is of crucial importance. Cellular senescence is a stable cell cycle arrest program that plays a dual role in GC. It exerts tumor-suppressive effects via growth arrest but also promotes tumor progression and immune evasion by remodeling the tumor microenvironment (TME) through senescence-associated secretory phenotype (SASP). This review comprehensively elucidates the molecular mechanisms of cellular senescence in GC and the core regulatory networks involving gene regulation, epigenetic modifications, metabolic reprogramming, and cell cycle arrest. Additionally, the review highlights how senescent cells foster an immunosuppressive microenvironment via SASP, forming a self-reinforcing feed-forward loop. Regarding therapeutic strategies, we summarize potential approaches targeting cellular senescence, including senescence induction, senescent cell clearance, SASP modulation, and multi-target synergistic therapy by integrating epigenetic regulation, metabolic intervention, and immune microenvironment modulation. Despite progress, numerous challenges remain. Future studies should leverage multi-omics technologies, novel models' development, and large-scale clinical trials to advance the clinical translation of GC cellular senescence research, providing new insights for improving prognosis.

PMID:41910653 | DOI:10.14336/AD.2025.1571

Cells. 2026 Mar 17;15(6):535. doi: 10.3390/cells15060535.

ABSTRACT

Gastric cancer (GC) remains a major global health burden, with its unfavorable prognosis primarily driven by extensive tumor heterogeneity. Traditional bulk omics, while informative, are inherently limited by the averaging effect of diverse cell populations and fail to capture the critical spatial molecular disparities within the tumor and its microenvironment (TME). Single-cell omics can capture cellular heterogeneity but lack spatial context. Therefore, there is an urgent clinical need for spatial multi-omics to provide a high-definition dissection of GC heterogeneity and to optimize therapeutic efficacy. This review first outlines briefly the evolution of spatial technologies, including transcriptomics, proteomics, metabolomics, genomics and epigenomics, and their transformative applications in GC research. We further explore how these platforms refine molecular classification beyond traditional models, identify next-generation biomarkers, and decode the intricate cellular interactions governing immune evasion and metastasis. Next, we highlight the pivotal role of spatial profiling in unravelling the multidimensional mechanisms of resistance to chemotherapy, targeted therapy and immunotherapy. Finally, we address current technical bottlenecks and discuss prospects for clinical translation.

PMID:41892326 | PMC:PMC13025482 | DOI:10.3390/cells15060535

Biochem Biophys Rep. 2026 Mar 16;46:102537. doi: 10.1016/j.bbrep.2026.102537. eCollection 2026 Jun.

ABSTRACT

BACKGROUND: Although studies have shown that the androgen receptor (AR) is associated with tumor progression and malignant regulation, its role in the tumor immune microenvironment and predictive value for prognosis and immunotherapy response in various cancer types have not been systematically analyzed.

METHODS: In this paper, multi-omics techniques was used to analyze AR comprehensively.

RESULTS: A comprehensive pan-cancer analysis revealed that the AR was expressed in a variety of tumors, especially as a risk factor for poor prognosis in gastric cancer. In addition, gene set enrichment analysis showed that the AR promotes cell proliferation and tumor cell invasion and regulates anti-tumor response. Immune score, immune cell infiltration, and anticancer immune cycle analysis showed that high AR levels were correlated with low infiltration of CD4⁺ T cells and NKT cells, high infiltration of Th2 cells and MDSCs, negatively correlated with antigen-presenting molecules, and positively correlated with various immune-negative regulatory molecules. Single-cell sequencing highlighted the heterogeneous expression of ARs in different cell types, particularly in epithelial cells, where high AR levels were associated with the enhanced activity of tumor-promoting pathways.

CONCLUSIONS: In conclusion, this study highlights the potential of the AR as a novel biomarker for gastric cancer prognosis and immunotherapy efficacy, expanding its applicability in the development of new antitumor drugs.

PMID:41890218 | PMC:PMC13014673 | DOI:10.1016/j.bbrep.2026.102537

Cell Oncol (Dordr). 2026 Mar 23;49(2):60. doi: 10.1007/s13402-026-01194-6.

ABSTRACT

Glycolytic reprogramming is closely associated with the occurrence and progression of gastric cancer. Specifically, the energy derived from glucose metabolism and the cellular proteins by its intermediate products influence gastric cancer development. However, as an important branch of glucose metabolism, sialic acid metabolism and its mediated sialylation modifications remain insufficiently studied in gastric cancer, and their specific relationship with malignant tumor progression requires further exploration. This study employed a multi‑omics approach, integrating metabolomics, single‑cell RNA sequencing, and bulk RNA sequencing analyses, to investigate the metabolic landscape of gastric cancer and its associated alterations. The results indicated that sialic acid is a characteristic metabolite in malignant gastric cancer tissues. It modulates biological functions such as immune response, proliferative activity, and metabolic remodeling within gastric cancer tissues by influencing sialylation modifications. Furthermore, we identified the drug WZ35, which can inhibit the malignant proliferation of gastric cancer by targeting both sialic acid metabolism and sialylated protein modifications. We put forward a conjecture that the metabolism and modification of sialic acid promote the malignant development of gastric cancer, and we discovered that the drug WZ35 has an inhibitory effect on the sialic acid metabolism of gastric cancer.

GRAPHICAL ABSTRACT:

PMID:41870836 | PMC:PMC13009457 | DOI:10.1007/s13402-026-01194-6

In Vitro Cell Dev Biol Anim. 2026 Mar 18. doi: 10.1007/s11626-026-01151-5. Online ahead of print.

ABSTRACT

Stress is a key trigger of gastric dysmotility, partly via mitochondrial dysfunction and disordered gut-brain hormonal signaling. Xinwei Tang (XWT) is a multi-herb formula used empirically for upper gastrointestinal symptoms, but its mechanisms remain unclear. This study aimed to determine whether XWT alleviates water-immersion restraint stress (WIRS)-induced gastric dysmotility and to delineate underlying mitochondrial and metabolic pathways using integrated in vivo, in vitro and multi-omics approaches. Male rats underwent 7-d WIRS and received vehicle, domperidone (3 mg/kg) or XWT (3, 6, 12 g/kg). Gastric emptying, serum motilin/gastrin, oxidative stress indices and PINK1/Parkin-LC3/p62 proteins were assessed, and H₂O₂-injured GES-1 cells were treated with XWT-medicated serum. Gastric antra from MOD and XWT-H rats were analyzed by RNA-seq and DIA proteomics (n = 3/group). WIRS reduced gastric emptying by roughly half and lowered motilin/gastrin, increased ROS/MDA and disrupted PINK1/Parkin-LC3/p62 profiles; XWT dose-dependently reversed these changes, with XWT-H approximating domperidone. Omics revealed XWT-associated downregulation of inflammatory/protease and acute-phase genes/proteins and enrichment of oxidative phosphorylation, tricarboxylic-acid cycle and other metabolic pathways, without global activation of canonical autophagy/mitophagy gene sets. These preclinical data indicate that XWT ameliorates stress-induced gastric dysmotility via mitochondria- and metabolism-centred protection with selective tuning of mitophagy-related proteins.

PMID:41851413 | DOI:10.1007/s11626-026-01151-5

J Proteome Res. 2026 Apr 3;25(4):2014-2023. doi: 10.1021/acs.jproteome.5c00983. Epub 2026 Mar 17.

ABSTRACT

OBJECTIVE: 19-Hydroxybufalin (19-H) is a natural bioactive compound with anticancer potential, but its molecular target and mechanism of action remain unclear. This study aimed to systematically evaluate its antigastric cancer activity and identify potential molecular targets.

METHODS: The antitumor effect of 19-H was evaluated in both in vitro and in vivo models. Multiomics analysis, thermal proteome profiling, molecular docking, and molecular dynamics simulations were employed to elucidate the mechanism of action. Functional assays were further conducted to validate the key target.

RESULTS: 19-H exhibited nanomolar-level inhibitory activity against various gastric cancer cell lines, significantly suppressing tumor growth in subcutaneous xenograft and patient-derived xenograft models. Multiomics analysis revealed that 19-H reshaped metabolic pathways in gastric cancer. TPP screening identified PLPP2 as a potential target with significantly increased thermal stability upon 19-H treatment. Molecular simulations further revealed that 19-H binds stably to the α-helical region of PLPP2.

CONCLUSIONS: 19-H exerts its antigastric cancer effect by targeting PLPP2 and remodeling the metabolic network. PLPP2 may represent a novel therapeutic target for gastric cancer.

PMID:41842934 | DOI:10.1021/acs.jproteome.5c00983

J Int Med Res. 2026 Mar;54(3):3000605261430163. doi: 10.1177/03000605261430163. Epub 2026 Mar 16.

ABSTRACT

ObjectiveTo explore the potential involvement of PANoptosis-related genes in gastric cancer susceptibility through multiomics analyses.MethodsSummary-data-based Mendelian randomization was performed by integrating blood-derived methylation, gene expression, and protein quantitative trait loci data with genome-wide association study results. The findings were further evaluated in The Cancer Genome Atlas cohort, followed by protein-protein interaction analysis, drug prediction, and molecular docking.ResultsSummary-data-based Mendelian randomization and colocalization analyses identified several traits suggestively associated with gastric cancer risk. Genetically predicted higher expression of apoptosis and caspase activation inhibitor (AVEN) and hepatocyte growth factor (HGF) as well as higher HGF protein levels were associated with increased risk, whereas higher levels of protein phosphatase 2 regulatory subunit B beta (PPP2R2B) appeared to be protective. Multiomics integration suggested epigenetic regulation of HGF and PPP2R2B. The Cancer Genome Atlas analysis corroborated the dysregulation of these candidates, with high AVEN expression associated with poorer survival. Protein-protein interaction and drug prediction analyses highlighted functional networks and potential therapeutics, supported by molecular docking demonstrating strong HGF-binding affinities. However, these associations did not reach statistical significance in the independent validation cohort, possibly due to limited statistical power.ConclusionsThis study identified AVEN, HGF, and PPP2R2B as potential candidate genes for gastric cancer. These findings require further validation in larger cohorts.

PMID:41840829 | DOI:10.1177/03000605261430163

Int J Mol Sci. 2026 Feb 25;27(5):2171. doi: 10.3390/ijms27052171.

ABSTRACT

Gastric cancer (GC), also known as stomach adenocarcinoma (STAD), remains a highly lethal malignancy due to late diagnosis, limited therapeutic efficacy, and frequent metastasis. Although extensive molecular profiling has been performed, post-transcriptional regulatory mechanisms underlying GC progression are still incompletely characterized. In this study, we applied an integrative multi-omics framework to elucidate the regulatory roles and clinical relevance of circular RNAs (circRNAs) in GC. Transcriptomic data of mRNAs, microRNAs, and circRNAs from eight independent GEO datasets were jointly analyzed, resulting in the identification of 249 differentially expressed genes (DEGs), 8 differentially expressed microRNAs (DEmiRNAs), and 4 differentially expressed circRNAs (DEcircRNAs). These molecules were integrated into a competing endogenous RNA (ceRNA) network, enabling systems-level characterization of GC-associated regulatory interactions. Network topology and survival analyses prioritized 13 hub molecules, including IGF2BP3, COL4A1, MMP14, and TGM2, which showed both central network positions and significant associations with patient survival. To explore therapeutic implications, transcriptomics-guided drug repositioning combined with molecular docking analysis identified five candidate compounds-celastrol, fedratinib, pevonedistat, tozasertib, and withaferin A-predicted to target key network hubs. Overall, this in silico study provides a ceRNA-centered regulatory framework for GC and prioritizes biologically informed biomarkers and repositioned drug candidates with potential applicability across other malignancies to converge precision oncology.

PMID:41828401 | PMC:PMC12985316 | DOI:10.3390/ijms27052171

Tissue Cell. 2026 Mar 10;101:103409. doi: 10.1016/j.tice.2026.103409. Online ahead of print.

ABSTRACT

Gastric cancer (GC) remains a major global health burden, with high incidence and mortality rates, particularly in East Asia, driven by factors such as Helicobacter pylori infection, dietary risks, and genetic predispositions. Conventional treatments like surgery and chemotherapy are limited by resistance, toxicity, and poor outcomes in advanced stages. The PI3K/Akt/mTOR and MAPK signaling pathways are central to GC pathogenesis, promoting proliferation, survival, metabolic reprogramming, epithelial-mesenchymal transition (EMT), and metastasis through aberrations like PIK3CA mutations, PTEN loss, and KRAS alterations. These pathways exhibit extensive crosstalk, contributing to therapeutic resistance. This review explores the regulatory effects of Traditional Chinese Medicine (TCM) on these pathways in GC, grounded in TCM principles such as Qi deficiency, Damp-Heat, and disharmony of the Spleen and Stomach. Single herbal monomers (e.g., curcumin, berberine, resveratrol) inhibit PI3K/Akt/mTOR by upregulating PTEN and suppressing mTOR, inducing autophagy and apoptosis. Classical herbs like Huangqin and Huanglian modulate Akt and ERK phosphorylation, while compound formulas (e.g., Banxia Xiexin Decoction, Sijunzi Decoction) synergistically target both pathways, reversing EMT and chemoresistance. TCM addresses crosstalk by disrupting feedback loops and reducing inflammation, enhancing efficacy in combination with Western therapies like chemotherapy and immunotherapy. Network pharmacology and multi-omics analyses reveal TCM's multitarget mechanisms, aligning with ZHENG-based personalization. Challenges include research variability, standardization issues, and incomplete mechanistic validation. Future directions emphasize high-quality trials, omics integration, and precision TCM for clinical translation. TCM offers low-toxicity, holistic options for integrative GC management, potentially improving survival and quality of life.

PMID:41825157 | DOI:10.1016/j.tice.2026.103409

Gastric Cancer. 2026 Mar 13. doi: 10.1007/s10120-026-01718-x. Online ahead of print.

ABSTRACT

BACKGROUND: 5-Fluorouracil (5-FU) remains a cornerstone of first-line chemotherapy for gastric cancer, yet the emergence of resistance severely compromises its clinical efficacy. Although ferroptosis suppression has been recognized as a pivotal mechanism of chemoresistance, the mitochondrial regulatory processes involved remain poorly understood.

METHODS: We integrated clinical specimen analysis, in vitro and in vivo functional assays, multi-omics profiling, and molecular docking to delineate the role of the mitochondrial oxidoreductase OXNAD1 in mediating 5-FU resistance in gastric cancer, and to assess the therapeutic potential of the natural polyphenol resveratrol as a chemosensitizing agent.

RESULTS: OXNAD1 was found to be significantly overexpressed in gastric cancer tissues and cell lines, correlating with unfavorable prognosis and enhanced 5-FU resistance. Mechanistically, OXNAD1 directly bound to and suppressed the ferroptosis driver PTGS2, thereby attenuating lipid peroxidation and mitochondrial damage, ultimately restraining ferroptosis and promoting drug resistance. Notably, resveratrol disrupted the OXNAD1-PTGS2 interaction by directly binding OXNAD1, reinstating ferroptotic activity, markedly enhancing the cytotoxic effect of 5-FU in resistant cells, and potentiating the antitumor efficacy of 5-FU in xenograft models.

CONCLUSION: The OXNAD1-PTGS2 axis constitutes a critical metabolic-cell death cross-regulatory pathway underlying 5-FU resistance in gastric cancer. Targeting this axis with resveratrol provides a promising combinatorial strategy to overcome chemoresistance.

PMID:41824193 | DOI:10.1007/s10120-026-01718-x

Mol Divers. 2026 Mar 12. doi: 10.1007/s11030-026-11508-3. Online ahead of print.

ABSTRACT

Gastric cancer (GC) risk is shaped by environmental exposures such as benzo[a]pyrene (BaP). Here, we systematically identified BaP-toxicological targets and dissected their contribution to GC development. BaP-related targets were independently predicted with stringent filters from ChEMBL, Similarity Ensemble Approach (SEA) and PharmMapper databases, while GC-related targets were mined from the Comparative Toxicogenomics Database (CTD), GeneCards and OMIM databases. Overlapping targets were subjected to protein-protein interaction (PPI) network construction, functional enrichment analysis and molecular docking. We then integrated multi-omics data using ten clustering algorithms to identify the consensus GC subtypes, which were subsequently employed 101 machine learning combinations to develop a consensus benzo[a]pyrene-related signature (CBRS) for GC patients. As a result, we identified seven hub toxicological targets: ALB, HSP90AA1, ESR1, INS, TP53, TNF, and EGFR, underscoring their potential central roles in BaP-driven GC pathogenesis. These targets are enriched in the MAPK, Lipid and atherosclerosis, and PI3K-Akt signaling pathway. The BaP-toxicological classifiers and the CBRS prognostic model could provide useful support for risk stratification and inform personalized therapeutic strategies for GC patients. Molecular docking results suggest that BaP exhibits relatively strong binding affinity with these key toxicological targets, potentially implicating their involvement in BaP-induced gastric cancer toxicity. Therefore, this study integrates multi-dimensional omics data with advanced machine learning algorithms to establish a comprehensive analytical framework for the toxicological effects of between BaP and GC, which transcends the limitations of traditional analyses and offers unprecedented insights and evidence chains for elucidating the pathogenesis of GC.

PMID:41817952 | DOI:10.1007/s11030-026-11508-3