Background and aim Helicobacter pylori driven gastric carcinogenesis contributes to stomach adenocarcinoma (STAD) through chronic inflammation, immune dysregulation, and tumour progression. This study aimed to identify H. pylori associated therapeutic targets and evaluate repurposed anticancer drugs through integrated computational and experimental approaches.
Methodology Differentially expressed genes from TCGA-STAD were filtered for H. pylori associated gene signatures using the Xena Browser. Gene expression, survival, network, and immune infiltration analysis were used for target prioritization. FDA-approved and clinical stage anticancer small molecules were screened by molecular docking, followed by 100-ns molecular dynamics (MD) simulations, principal component analysis (PCA), dynamic cross-correlation matrix (DCCM), and Prime MM-GBSA analysis. Experimental validation was performed in AGS cells using MTT, quantitative RT-PCR, and Western blotting.
Results Among 250 upregulated genes, 11 genes were associated with H. pylori positive STAD. TREM2 was prioritized based on overexpression, network connectivity, immune infiltration profile, and biological relevance, despite showing trend towards poor survival (HR = 1.20, p = 0.056). TREM2 expression was positively associated with immune-cell populations. Molecular docking identified Lerociclib as the top ranked compound interacting with TREM2 through hydrogen bonds involving Asn79, Ser81, and Asp104, along with hydrophobic and van der Waals interactions. MD, PCA, DCCM, and MM-GBSA analyses supported stable binding and coordinated residue dynamics. Lerociclib reduced cell viability and decreased TREM2 mRNA and protein expression in AGS cells.
Conclusion This study identifies TREM2 as a promising therapeutic target in H. pylori associated STAD, while Lerociclib emerges as repurposed compound for TREM2. Further mechanistic and preclinical evaluation is required in gastric cancer.
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