The PTM switches of HBx: Master regulators of HBV infection and liver oncogenesis.

The hepatitis B virus (HBV) X protein (HBx) functions as a versatile regulatory molecule that is indispensable for both efficient HBV replication and the pathogenesis of HBV-related hepatocellular carcinoma (HCC). Accumulating studies indicate that a broad spectrum of post-translational modifications (PTMs), including ubiquitination, phosphorylation, NEDDylation and ISGylation, critically influence HBx stability, intracellular trafficking, and its capacity to engage with diverse host factors. Collectively, these PTMs constitute a complex modulatory network that governs viral persistence and contributes to malignant transformation in the liver. In this review, we synthesize recent advances in deciphering the molecular principles that drive HBx PTMs and delineate their functional consequences during HBV infection and HCC development. We also summarize current understanding of how HBV manipulates host PTM systems to optimize its life cycle while promoting oncogenic processes. Furthermore, the review discusses emerging therapeutic opportunities centered on modulating HBx PTMs, with the aim of informing the design of next-generation antiviral and anti-tumor interventions.