Causal Relationships Between Plasma Metabolites, Inflammatory Factors, and Oral Cancer Risk: A Comprehensive Mendelian Randomization Study With Mediation Analysis.

This study conducted a large-scale Mendelian randomization analysis using genome-wide single nucleotide polymorphisms (SNPs) as instrumental variables to investigate the causal relationships between 1400 circulating metabolites and oral cancer risk. The genetic data were derived from the Canadian Longitudinal Study on Aging (CLSA) cohort and the IEU OpenGWAS database. The study employed germline genetic variants captured in genome-wide association studies for causal inference, combined with mediation analysis and CAL-27 cell experimental validation. The results identified 61 metabolites with significant causal relationships with oral cancer through SNP instrumental variables (29 with protective effects and 32 increasing risk) and revealed 14 inflammatory factors as key mediating variables, with mediation effects accounting for 1.4%-17.4% of the total effects. Cell experiments further confirmed that aspartate significantly downregulates CCL11 expression and secretion and exerts anti-inflammatory effects by suppressing inflammatory factors, including IL-1β, IL-6, and TNF-α. Conversely, CCL11 overexpression promotes malignant cellular behavior, but these effects can be reversed by aspartate through inhibition of NF-κB and MAPK signaling pathways. This study elucidates a genetic variant-driven "metabolism-inflammation" carcinogenic pathway, providing novel insights into the mechanisms of oral cancer development and demonstrating significant translational potential for precision prevention and precision therapy.