Metabolome‐Wide Mendelian Randomization Identifies Maleate as a Mediator of the Effect of Obesity on the Risk of Small Cell Lung Cancer

Obesity is a well-established risk factor for numerous types of cancer, including small cell lung cancer (SCLC). However, the underlying mechanisms remain largely unclear. This research explores the causal relationships between obesity, circulating metabolites, and the risk of SCLC, aiming to identify potential metabolic intermediaries. To achieve this, a two-step Mendelian randomization (MR) approach was employed to examine metabolites mediating the effect of obesity on the risk of SCLC. In Step 1, MR identified metabolites causally associated with SCLC, confirmed with an independent SCLC genome-wide association study (GWAS) as the outcome. In Step 2, whole-body fat mass was examined as the exposure to assess its causal effects on the metabolites identified in Step 1, with further validation using body mass index (BMI) as an alternative exposure. Sensitivity analyses confirmed robust causal inference. The product of coefficients approach for testing mediation quantified the role of specific metabolites in linking obesity to the risk of SCLC. In the initial screening, 1400 circulating metabolites were tested for their association between obesity and the risk of SCLC, and 55 metabolites with significant causal associations were identified. Subsequent MR analyses showed that whole-body fat mass had an effect on 12 of these metabolites, and maleate levels were associated with both obesity and increased SCLC risk. Validation using BMI as an alternative exposure confirmed the causal association between obesity and maleate levels. Further validation using independent GWAS datasets for SCLC confirmed the causal association between maleate levels and the risk of SCLC. Mediation analysis revealed that maleate partially mediated the relationship between obesity and the risk of SCLC, accounting for 14.9% of the effect when using whole-body fat mass as the exposure and 5.23% when using BMI as the exposure. This study highlights maleate as a key metabolic mediator in the obesity-SCLC pathway, which may offer novel insights into the metabolic mechanisms underlying the increased risk of obesity-related cancer.