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Microbiome dysbiosis has been linked to creating a favorable environment for cancer development by disrupting immune responses, altering hormone metabolism, and affecting cell cycle regulation and apoptosis. Notably, studies have explored the connection between the gut microbiome and EC. Our study employs a Mendelian randomization (MR) approach, utilizing genetic variants as instrumental variables, to investigate the causal associations between gut microbiota, plasma metabolites, and EC. Our findings revealed 16 mediation pathways involving 4 microbial species and 14 plasma metabolites, highlighting potential connections between gut microbiota and EC, with some metabolites such as Carboxyethyl-GABA and Glycodeoxycholate 3-sulfate mediating the effects of gut microbiota on EC.Our research provides novel insights into the causal relationship between the gut microbiota, plasma metabolites, and EC, indicating potential targets for intervention in the disease. We are convinced that these discoveries hold substantial relevance for the domain of gynecological oncology research and clinical practice, potentially exerting a significant impact on the prevention and therapeutic strategies for EC.