Simple SummaryLiver cancer is a prevalent gastrointestinal carcinoma and is closely linked to chronic inflammation, including both hepatic and extrahepatic inflammations. However, the genetic association between inflammatory traits and liver cancer has not been systematically investigated. In this study, we aimed to explore the potential causal associations between immune-mediated diseases, circulating inflammatory biomarkers and cytokines, and liver cancer using Mendelian randomization (MR) analysis. To our best knowledge, this is the most comprehensive MR study on this topic to date, involving more than 200 inflammatory traits. This is an important contribution to the field, as it provides insights into the potential causal inflammatory factors of liver cancer.AbstractLiver cancer is closely linked to chronic inflammation. While observational studies have reported positive associations between extrahepatic immune-mediated diseases and systemic inflammatory biomarkers and liver cancer, the genetic association between these inflammatory traits and liver cancer remains elusive and merits further investigation. We conducted a two-sample Mendelian randomization (MR) analysis, using inflammatory traits as exposures and liver cancer as the outcome. The genetic summary data of both exposures and outcome were retrieved from previous genome-wide association studies (GWAS). Four MR methods, including inverse-variance-weighted (IVW), MR-Egger regression, weighted-median, and weighted-mode methods, were employed to examine the genetic association between inflammatory traits and liver cancer. Nine extrahepatic immune-mediated diseases, seven circulating inflammatory biomarkers, and 187 inflammatory cytokines were analyzed in this study. The IVW method suggested that none of the nine immune-mediated diseases were associated with the risk of liver cancer, with odds ratios of 1.08 (95% CI 0.87–1.35) for asthma, 0.98 (95% CI 0.91–1.06) for rheumatoid arthritis, 1.01 (95% CI 0.96–1.07) for type 1 diabetes, 1.01 (95% CI 0.98–1.03) for psoriasis, 0.98 (95% CI 0.89–1.08) for Crohn’s disease, 1.02 (95% CI 0.91–1.13) for ulcerative colitis, 0.91 (95% CI 0.74–1.11) for celiac disease, 0.93 (95% CI 0.84–1.05) for multiple sclerosis, and 1.05 (95% CI 0.97–1.13) for systemic lupus erythematosus. Similarly, no significant association was found between circulating inflammatory biomarkers and cytokines and liver cancer after correcting for multiple testing. The findings were consistent across all four MR methods used in this study. Our findings do not support a genetic association between extrahepatic inflammatory traits and liver cancer. However, larger-scale GWAS summary data and more genetic instruments are needed to confirm these findings.