نبذة مختصرة : Abstract Background Evidence from observational studies suggests an association between free cholesterol and gastric cancer. Immune cells play a crucial role in the tumor microenvironment of gastric cancer, and free cholesterol can influence immune cells in various ways, thereby impacting gastric cancer. The mechanisms by which free cholesterol regulates and activates the immune response to exert antitumor effects, as well as the causal relationship between free cholesterol and gastric cancer, remain unclear. Methods We employed a two-sample Mendelian randomization (MR) approach to investigate the causal relationship between 233 metabolites and gastric cancer. Additionally, we validated our findings using data from GWAS databases of similar traits. Using publicly available genetic data, we analyzed the causal relationship between 731 types of immune cells and gastric cancer. Furthermore, we explored the mediating role of regulatory T cells in the causal relationship between free cholesterol and gastric cancer through multivariable Mendelian randomization. Finally, we validated our results using data from the TCGA database and single-cell sequencing data. Findings We found a causal relationship between free cholesterol levels and gastric cancer (odds ratio [OR] = 0.89, confidence interval [CI] = 0.81–0.98, P
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