The Ubiquitin-Proteasome System in Hepatitis B Virus Infection and Hepatocarcinogenesis: Viral Manipulation and Therapeutic Targets.

Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma. To sustain viral life cycle, HBV modulates host pathways controlling protein turnover and innate immunity. Critical events in the HBV life cycle include the conversion of relaxed-circular DNA to covalently closed circular DNA, transcriptional activation of viral genes, and the synthesis and maturation of structural and regulatory proteins. These processes are tightly linked to the ubiquitin-proteasome system (UPS), the central machinery for post-translational control. Disruption of UPS homeostasis impairs antiviral signaling and drives malignant progression. Among HBV proteins, HBV X protein reshapes protein ubiquitination by recruiting or redirecting host E3 ligases. These alterations elevate the stability of virus-facilitating mediators, downregulate interferon-stimulated responses, and expedite the turnover of key tumor suppressors. In parallel, the host counters by attaching degradative ubiquitin chains to viral antigens or downregulating proviral modifications through deubiquitinases (DUBs). In this review, we consolidate current knowledge of the HBV-UPS interplay, dissecting molecular circuits that govern ubiquitin-driven degradation and detailing the specific E3 ligases hijacked by the virus. Finally, we evaluate therapeutic potentials that target HBV-UPS interaction, ranging from broad-spectrum proteasome inhibitors and selective DUB antagonists to proteolysis targeting chimeras.