Host restriction factors in HBV-related liver disease and hepatocellular carcinoma: mechanisms of viral-host interplay and implications for therapy.

Chronic hepatitis B virus (HBV) infection is a leading cause of liver cirrhosis and hepatocellular carcinoma (HCC), imposing a substantial global health burden. The natural history of persistent HBV infection progresses from chronic inflammation to fibrosis, cirrhosis, and malignant transformation, driven in part by the stability of covalently closed circular DNA (cccDNA) within hepatocyte nuclei. Nucleos(t)ide analogues (NUCs) effectively suppress viral replication but rarely lead to a functional cure, necessitating long-term therapy and carrying a residual risk of resistance. PEG-interferon-α can induce a functional cure in a minority of patients but its clinical use is limited by frequent adverse effects. Host restriction factors-cellular proteins that directly inhibit viral replication-act at multiple stages of the HBV infection cycle, including entry, cccDNA transcription, RNA stability, and virion release. HBV counters these intrinsic defenses through viral proteins such as HBx, establishing a dynamic interplay between viral and host factors that shapes infection outcome and disease progression. This review consolidates recent advances in understanding the roles of host restriction factors in HBV pathogenesis and their mechanistic links to cirrhosis and HCC. We also highlight emerging therapeutic strategies aimed at targeting these host-virus interactions to disable HBV persistence, and thereby reduce HBV-related disease burden.