Mendelian Randomization Study Reveals Gut Microbiota Modulates Hepatocellular Carcinoma via Ferroptosis and Pyroptosis Pathways: Highlighting the Pivotal Mediating Role of PARK7

The pathogenesis of hepatocellular carcinoma (HCC) involves complex interactions between the gut microbiota (GM) and cell death pathways, although the causal mechanisms remain elusive. Using a two-sample Mendelian randomization (MR) framework, we systematically interrogated the causal chain linking GM dysbiosis to HCC by modulating ferroptosis and pyroptosis. Analyzing genetic variants of 5,959 individuals (473 microbial taxa) and HCC GWAS data, we identified 19 GM taxa with causal effects on HCC: 9 risk-enhancing (e.g. Omnitrophota, OR = 9.53, P = 0.002) and 10 protective (e.g. Endozoicomonadaceae, OR = 0.44, P = 0.022). Ferroptosis-related genes (HSPA5, PARK7) and pyroptosis-linked ELANE mediated these effects, with PARK7 showing mediation (13.61%) and prognostic significance (5-year survival, P=1.80e-04). Single cell profiling revealed overexpression of PARK7 in stem-like HCC cells (e.g. JHH-7), suggesting its role in microbiota-driven ferroptosis activation. Sensitivity analyzes confirmed robustness against pleiotropy and reverse causation. Our findings establish a microbiota–cell death–HCC axis, nominating PARK7 as a therapeutic target and microbiome modulation as a preventive strategy.