HCV-Induced Hepatocarcinogenesis: Molecular Mechanisms, Persistent Cancer Risk, and Future Perspectives

Chronic infection with the hepatitis C virus (HCV) is the most significant risk factor for the development of hepatocellular carcinoma (HCC). It has been shown that the progression of HCV-related liver disease is mediated by both viral and host-specific factors. The HCV replication cycle is a host-dependent process that relies on intracellular signalling pathways within target cells. Thus, intracellular signal transduction plays a pivotal role in the modification of interactions between the host and HCV. These pathways are key regulators of liver diseases, including cirrhosis and HCC. In addition, HCV induces epigenetic modifications in the host genome that inhibit the expression of various tumour-suppressor genes. Some of these changes persist even after successful antiviral treatment and represent a continued risk for HCC development. Despite significant progress in the management of chronic HCV infection, this challenge remains unresolved. In this narrative review, we summarise the mechanisms of HCV-induced disease progression, focusing on the host immune response, the regulatory roles of viral and cellular proteins, and viral survival strategies during chronic infection. We also discuss HCV-induced epigenetic alterations that contribute to hepatocarcinogenesis both during infection and after viral clearance. These insights are important for identifying novel, reliable molecular biomarkers for patient surveillance and for designing new therapeutic approaches.