Metabolome‐Wide Mendelian Randomization Identifies Valine as a Potential Mediator of the Effect of Obesity on Pancreatic Cancer Risk

Obesity is a well-established risk factor for pancreatic cancer (PC), yet the underlying metabolic mechanisms that link obesity to increased PC risk remain unclear. This study aims to identify the specific metabolites mediating the relationship between obesity and pancreatic cancer. A two-sample two-step Mendelian randomization (MR) approach was used to determine the causal effects of circulating metabolites on PC risk and the causal effects of body mass index (BMI) on potential metabolites. Independent datasets were employed to validate the results from both steps. The mediation effect of the potential metabolites was quantified using the product of coefficients approach. Our study identified 55 circulating metabolites associated with PC risk through MR analysis, with no evidence of pleiotropy, heterogeneity, or reverse causality. Among them, 5 metabolites, including valine, showed a causal association with BMI. To validate our findings, Step 1 was replicated using an independent pancreatic cancer dataset from the UK Biobank, replacing the FinnGen cohort, while Step 2 was validated by substituting whole-body fat mass for BMI as the exposure; both analyses consistently confirmed the association with valine. Mediation analysis demonstrated that circulating valine levels partially mediated the effect of BMI on PC risk. The estimated mediated effect via valine was β = 0.064, corresponding to an approximate mediated proportion of 19.01%. This study reveals valine as a crucial metabolic mediator linking obesity to PC risk. The findings also underscore the complex interplay between obesity, metabolites, and cancer, offering new insights and avenues for PC research and treatment.