Gut microbiota's role in NAFLD- and HBV/HCV-related hepatocellular carcinoma: Mechanisms and therapeutic implications

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality globally and has been closely linked to chronic liver conditions, such as viral hepatitis and non-alcoholic fatty liver disease. Recent research has demonstrated that the gut microbiota significantly impacts the gut-liver axis, a crucial aspect of the pathophysiology of HCC. This review emphasizes the mechanisms by which gut dysbiosis contributes to liver inflammation, fibrosis, and tumor formation. In NAFLD-related HCC, modification in the microbiota composition facilitates intestinal barrier dysfunction, endotoxemia, and metabolic disturbances. In HCC associated with HBV/HCV, the microbiome modulates immune surveillance and viral persistence. Shared pathogenic pathways, such as LPS-TLR4 signaling, bile acid dysregulation, and immunosuppressive microenvironments, highlight the role of microbial imbalance across varied etiologies. We also discuss how antibiotics, diet, probiotics, and postbiotics influence gut-liver homeostasis, as well as their therapeutic potential in primary and secondary prevention and treatment of HCC. Short-chain fatty acids and valeric acid are examples of postbiotics with anti-inflammatory and pro-apoptotic anti-IBD effects, while fecal microbiota transplantation and dietary modulation have shown potential in improving outcomes. The review also identifies significant research gaps, particularly in establishing causality, understanding intrahepatic metastasis, and investigating the roles of the fungal and viral microbiome (mycobiome and virome). Finally, the incorporation of microbiome-based interventions into clinical practice could represent an effective future strategy for risk stratification, prevention, and adjuvant therapy of HCC. Future studies focusing on longitudinal analysis, mechanistic validation, and multi-kingdom profiling are essential for translating microbiome research into effective clinical applications.