Abstract
BACKGROUND: Ovarian cancer (OC), the deadliest gynecologic malignancy, lacks effective strategies for early detection and treatment. Emerging evidence suggests that the gut microbiota and inflammatory cytokines may influence OC pathogenesis, but the causal mechanisms remain unclear. This study employed a bidirectional, two-sample Mendelian randomization (MR) analysis with genetic mediation analysis to investigate whether genetically predicted inflammatory cytokines mediate the associations between the gut microbiota and OC. METHODS: This study was based on an analysis of public genetic summary statistics from predominantly European populations. The data from a genome-wide association study (GWAS) and public databases included 473 gut microbiotas (FinnGen, n = 5,959), 91 inflammatory cytokines (GWAS, n = 14,824), and 1,218 OC cases (UK Biobank). Inverse-variance weighted (IVW) was the primary MR method, supplemented by multiple methods such as MR-Egger and other sensitivity analyses to evaluate the robustness of findings. Single-nucleotide polymorphisms (SNPs) associated with exposure were selected as instrumental variables (IVs). Mediation analysis was conducted to explore the potential mediation effect of inflammatory cytokines. RESULTS: Our analysis identified 19 gut microbiotas (9 risk, 10 protective) and 5 inflammatory cytokines (4 risk, 1 protective) with associations suggestive of causality with OC under MR assumptions (P(FDR)<0.05). Mediation analysis revealed that interleukin-6 (IL-6) mediated 14.67% and 16.63% of the effects of Bacillaceae A and Prevotella sp000434975 on OC risk, respectively. Similarly, T-cell surface glycoprotein CD6 and leukemia inhibitory factor receptor (LIFR) accounted for 6.06% and 11.16% of the mediating effects for Bacillaceae A and Gluconobacter, respectively. Reverse MR suggested potential bidirectional interactions, with OC being associated with alterations in 18 gut microbiotas and 3 inflammatory cytokines. CONCLUSION: This MR study provides genetic evidence suggestive of a potential mechanism whereby the gut microbiota might influence OC risk partly through inflammatory cytokines, notably IL-6, CD6, and LIFR. These findings suggest these cytokines as potential risk markers and implicate pathways involving both microbiota modulation and cytokine activity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13048-026-01963-9.