Causal Interplay Between Inflammatory Cytokines and Lipid Metabolites in Serous Ovarian Carcinoma: Insights From a Genetic Association Study

BACKGROUND: The causal roles and interactions of inflammatory cytokines and metabolic reprogramming in serous ovarian carcinoma (SOC) remain unclear. This study explored their relationships using Mendelian randomization (MR). METHODS: In this two-sample MR analysis, GWAS data of inflammatory cytokines and blood metabolites were used as exposures, and SOC from the FinnGen consortium served as the outcome. Inverse variance weighted (IVW) was the primary MR method, supplemented by MR Egger, weighted median, simple mode, and weighted mode. Two-step mediation MR was applied to evaluate whether specific metabolites mediated the effect of inflammatory cytokines on SOC. Sensitivity analyses, including heterogeneity and pleiotropy tests, were conducted to assess robustness. RESULTS: Five inflammatory cytokines were identified as risk factors for SOC: CSF1 (OR = 1.69, 95% CI: 1.17-2.43), CXCL1 (OR = 1.40, 95% CI: 1.01-1.93), IL-20 (OR = 1.86, 95% CI: 1.03-3.35), IL-8 (OR = 1.61, 95% CI: 1.08-2.39), and VEGF-A (OR = 1.24, 95% CI: 1.00-1.54). Furthermore, 1-Palmitoyl-GPG (16:0) potentially mediates the relationship between IL-8 and SOC, explaining ~10% of the total effect. No pleiotropy or heterogeneity was detected. CONCLUSIONS: This two-sample MR study provides preliminary genetic evidence that inflammatory cytokines contribute to SOC risk, with lipid metabolism partially mediating IL-8 effects. These findings highlight the interplay between inflammation and metabolism in SOC pathogenesis and suggest potential biomarkers and therapeutic targets. Due to limited sample sizes and European-only ancestry datasets, these findings require validation in larger, multi-ancestry cohorts.