Abstract
PURPOSE: While observational studies have identified obesity as a potential risk factor for gastric cancer, the causality remains uncertain. This study aimed to evaluate the causal relationship between obesity and gastric cancer and identify the shared molecular signatures linking obesity to gastric cancer. METHODS: A two-sample Mendelian randomization (MR) analysis was conducted using the GWAS data of body fat percentage (exposure, n = 331,117) and gastric cancer (outcome, n = 202,308). Bioinformatics and meta-analysis of multi-omics data were performed to identify key molecules mediating the causality. The meta-analysis of the plasma/serum proteome included 1,662 obese and 3,153 gastric cancer patients. Obesity and gastric cancer-associated genes were identified using seven common gene ontology databases. The transcriptomic data were obtained from TCGA and GEO databases. The Bioinformatic findings were clinically validated in plasma from 220 obese and 400 gastric cancer patients across two hospitals. Finally, structural-based virtual screening (SBVS) was performed to explore the potential FDA-approved drugs targeting the identified mediating molecules. RESULTS: The MR analysis revealed a significant causal association between obesity and gastric cancer (IVW, OR = 1.37, 95% CI:1.12-1.69, P = 0.0028), without pleiotropy or heterogeneity. Bioinformatic and meta-analysis of multi-omics data revealed shared TNF, PI3K-AKT, and cytokine signaling dysregulation, with significant upregulation of AKT1, IL-6, and TNF. The clinical study confirmed widespread upregulation of systemic inflammatory markers in the plasma of both diseases. SBVS identified six novel potent AKT1 inhibitors, including the dietary supplement adenosine, representing a potentially preventive drug with low toxicity. CONCLUSION: Obesity causally increases gastric cancer, likely mediated by persistent AKT1/IL-6/TNF upregulation. As a potential AKT1 inhibitor, adenosine may mitigate the obesity-to-gastric cancer transition. These findings could inform preventive drug development to reduce gastric cancer risk in obesity.