Int J Chron Obstruct Pulmon Dis. 2026 Apr 7;21:561645. doi: 10.2147/COPD.S561645. eCollection 2026.

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a systemic condition with comorbidities beyond the lung (eg, cardiovascular and metabolic disorders), and gastrointestinal (GI) disorders are also common. The shared genetic basis of COPD-GI comorbidity and its mediating factors remain unclear. We hypothesized that COPD and GI diseases share pleiotropic genetic architecture implicating lipid-metabolic pathways, with smoking mediating part of the association.

METHODS: We analyzed publicly available European-ancestry GWAS summary statistics for COPD (Global Biobank Meta-analysis Initiative), 15 GI diseases (FinnGen), and smoking phenotypes (UK Biobank). Genetic correlation was estimated using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Multi-trait analysis of GWAS (MTAG) boosted COPD discovery by leveraging genetically correlated GI traits. We integrated locus-to-gene mapping with multi-tissue expression quantitative trait loci (eQTL) and plasma protein quantitative trait loci (pQTL) evidence to prioritize shared loci, genes, and proteins. Bidirectional two-sample Mendelian randomization (MR) tested causal directions, and two-step mediation MR evaluated smoking.

RESULTS: COPD showed significant genetic correlation with nine GI diseases. We identified six comorbidity-associated loci (three with CADD > 12.37) and 13 unique candidate pleiotropic genes; APOE was supported by proteomic evidence. Enrichment analyses highlighted lipid-metabolism pathways. MR suggested COPD increases risk of gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), acute appendicitis, and gastric ulcer, while diverticular disease showed reverse causality toward COPD. Smoking partially mediated the COPD effect on GERD, acute appendicitis, and gastric ulcer.

CONCLUSION: COPD and multiple GI disorders share a distributed pleiotropic genetic basis within the broader systemic comorbidity spectrum of COPD. Multi-omics evidence supports a genomic pulmonary-intestinal axis in which lipid metabolism and smoking-related mechanisms contribute to COPD and GI comorbidity, providing targets for risk stratification and potential intervention.

PMID:41978582 | PMC:PMC13070119 | DOI:10.2147/COPD.S561645

Int J Gen Med. 2026 Mar 24;19:590621. doi: 10.2147/IJGM.S590621. eCollection 2026.

ABSTRACT

Inflammatory bowel disease (IBD) involves chronic intestinal inflammation driven by gut-brain axis imbalance, fostering complications through an "inflammation-neuro-coagulation" triad. Current staging systems inadequately capture the dynamics of this multidimensional network. Therefore, integrated multi-omics analyses-including metagenomics, metabolomics, and single-cell transcriptomics-are essential to construct dynamic models that monitor coagulation, microbiome, and metabolism for precise assessment of disease activity and thrombotic or bleeding risks. Interventions targeting gut-brain axis nodes, such as eliminating tissue factor-positive (TF⁺) T cells or modulating vagal activity, show potential to disrupt the inflammation-coagulation cycle, although rigorous randomized trials are still needed. Artificial intelligence (AI)-assisted systems that integrate real-time biomarker monitoring with multi-omics predictions represent a novel paradigm for managing IBD-related coagulation dysfunction. Key challenges include elucidating gut-brain-liver axis regulation of coagulation and characterizing platelet functional heterogeneity. Future efforts must prioritize ethically compliant multi-omics platforms and racially stratified risk models to advance personalized coagulation management in IBD.

PMID:41913906 | PMC:PMC13033200 | DOI:10.2147/IJGM.S590621

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

FASEB J. 2026 Mar 31;40(6):e71634. doi: 10.1096/fj.202503587R.

ABSTRACT

Gastric cancer (GC) is a leading cause of cancer-related deaths and has high recurrence rate. Although fibronectin domain-containing protein 1 (FNDC1) is implicated in GC progression, its molecular mechanisms remain unclear. Multi-omics analyses (TCGA, GEO datasets) were used to assess FNDC1 expression and clinical correlation. In vitro (cell proliferation, invasion, EMT markers) and in vivo (xenograft) experiments, combined with molecular assays (Co-IP, WB, ChIP), explored FNDC1's function and mechanism. FNDC1 was significantly upregulated in GC, correlating with advanced clinicopathological features and poor prognosis. Knockdown of FNDC1 suppressed GC cell proliferation, invasion, and metastasis by inhibiting EMT and Wnt/β-catenin signaling. Mechanistically, FNDC1 competitively bound the WD5 domain (residues 224-254) of Gβ2, disrupting Gβγ-Dvl1 interaction. This prevented Dvl1 degradation, promoted Axin1 ubiquitination, and destabilized the β-catenin-destruction complex (GSK3 β-APC-Axin1), leading to β-catenin accumulation and Wnt pathway activation. FNDC1 drives GC malignancy by targeting the Gβ2-Dvl1 axis to activate Wnt/β-catenin signaling, suggesting FNDC1 as a novel prognostic biomarker and therapeutic target.

PMID:41808415 | PMC:PMC12976582 | DOI:10.1096/fj.202503587R