Exploring Hepatocellular Carcinoma Etiology through Multi-omics Bioinformatics

Background Hepatocellular carcinoma (HCC) ranks as the sixth most common cancer globally, with increasing mortality and persistent therapeutic challenges. Emerging evidence suggests that the immune microenvironment, metabolic reprogramming, and gut microbiota dysbiosis play critical roles in HCC pathogenesis, though their causal effects are unclear. This study used Mendelian randomization (MR) to systematically assess these factors' causal relationships with HCC. Methods A two-sample MR analysis, integrated with meta-analysis, examined genetic data on 731 immune cell types, 91 immune factors, 1,400 metabolites, and 412 gut microbiota phenotypes. HCC outcome data were sourced from FinnGen (discovery) and UK Biobank (replication). Five MR methods—inverse-variance weighted, weighted median, MR-Egger, weighted mode, and simple mode—were applied, with rigorous sensitivity, heterogeneity, and reverse causation analyses to ensure validity. Results In the discovery stage, causal associations with HCC were identified for 4 immune cell phenotypes (3 protective, 1 pathogenic), 2 immune factors, 57 metabolites (24 pathogenic, 33 protective), and 105 gut microbiota phenotypes (51 pathogenic, 54 protective). Replication validated the metabolite 1-stearoyl-2-linoleoyl-GPC (18:0/18:2) and 6 gut microbiota phenotypes (4 protective, 2 oncogenic). Meta-analysis confirmed 2 protective immune cell phenotypes—CD20 on CD20- CD38- B cells and CD16-CD56 on NK cells—and 9 metabolites (3 protective, 6 oncogenic) as significant causal factors. Conclusion This study establishes causal links between specific immune cells, metabolites, and gut microbiota with HCC, revealing protective and oncogenic roles. These findings highlight potential biomarkers and therapeutic targets, advancing strategies for HCC prevention and personalized treatment.