Multidimensional analysis explores the correlation and potential molecular mechanisms between serum uric acid and risk of gastric cancer

Objective To investigate the causal association between SUA and gastric cancer risk and elucidate the underlying biological mechanisms. Methods A two-sample Mendelian randomization (MR) design was adopted. The inverse-variance weighted (IVW) method served as the primary analysis, supplemented by MR-Egger, weighted median, simple mode and weighted mode methods. Sensitivity analyses included the MR-Egger intercept test for horizontal pleiotropy, Cochran's Q -test for heterogeneity, and leave-one-out analysis. SNP-mapped genes were analyzed for expression profiles, prognostic value and functional enrichment in gastric cancer using TCGA data. In vitro validation was performed in uric acid-treated AGS gastric cancer cells to assess cell viability, apoptosis, oxidative stress markers and PI3K/AKT pathway activity. Results Genetically elevated SUA was causally associated with reduced gastric cancer risk in the IVW analysis (OR = 0.76, 95% CI: 0.62–0.92, p = 0.006), with consistent directional estimates across other MR methods. Sensitivity analyses indicated significant heterogeneity (Cochran's Q, p = 3.5 × 10⁻⁵) but no directional horizontal pleiotropy (MR-Egger intercept, p = 0.185). Two outlier SNPs were identified by MR-PRESSO, and outlier-corrected estimate remains significant (OR = 0.88, 95% CI: 0.77–1.00, p = 0.048), which confirmed the robustness of the SUA protective effects. Among 36 identified SNP-mapped genes, 25 were differentially expressed in gastric cancer, and 6 (ABCG2, BICC1, CFAP73, GNAS, MXD3, PNPLA3) were significantly associated with overall survival. These genes were enriched in uric acid metabolism, carboxylic acid transport and the mTOR signaling pathway. In vitro , uric acid dose-dependently inhibited proliferation, induced late apoptosis/necrosis, increased intracellular ROS, depleted antioxidant defenses, and suppressed PI3K/AKT pathway activity in AGS cells. Conclusions SUA exerts a protective causal effect against gastric cancer. The anti-tumor effect is mechanistically driven by oxidative stress induction and PI3K/AKT pathway inhibition, with SNP-associated genes linked to gastric cancer progression via metabolism-related signaling pathways.