Plasma metabolites may inhibit childhood obesity by regulating ferroptosis through SMPD1 and SIRT3.

OBJECTIVE: To investigate the causal relationship between plasma metabolites and ferroptosis-related genes in childhood obesity and to explore the potential mediating role of ferroptosis-related genes in the association between plasma metabolites and childhood obesity risk. METHODS: A bidirectional two-step Mendelian randomization (MR) approach was applied, leveraging publicly available genome-wide association study (GWAS) datasets to analyze the causal relationship among 1400 plasma metabolites, 159 ferroptosis-related genes, and childhood obesity. In the first step, protein quantitative trait loci (pQTL) data corresponding to ferroptosis-related genes were identified as mediators to evaluate the causal effects of plasma metabolites and ferroptosis-related genes on childhood obesity. In the second step, MR analysis was conducted on ferroptosis-related genes and plasma metabolites identified in the first step to confirm their causal association. The inverse-variance weighted (IVW) method was primarily used for meta-analysis, while MR-PRESSO was employed to detect pleiotropy and outliers. RESULTS: Four ferroptosis-related genes (SMPD1 and SIRT3 suppressing obesity, GSTZ1 and ADAMTS13 promoting obesity) and nine plasma metabolites were found to be significantly associated with childhood obesity (six negatively correlated and three positively correlated). Further mediation analysis indicated that the ferroptosis mechanism regulated by SMPD1 and SIRT3 partially mediated the association between specific plasma metabolites and childhood obesity, with the highest mediation proportion reaching 9.62%. Sensitivity analysis confirmed the robustness of the results (no heterogeneity or horizontal pleiotropy), and reverse Mendelian randomization ruled out causal interference. CONCLUSION: This study is the first to reveal, through Mendelian randomization analysis, the potential mediating role of ferroptosis-related genes in the association between plasma metabolites and childhood obesity. It suggests that the ferroptosis mechanism may influence childhood obesity risk by regulating specific metabolites. These findings contribute to understanding the role of ferroptosis in the pathological mechanisms of childhood obesity and provide novel molecular targets and intervention strategies for obesity prevention and treatment in children.