HBx Protein in Hepatitis B Virus-Related Hepatocellular Carcinoma: Pathogenic Mechanisms and Emerging Interventions

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, most commonly driven by chronic hepatitis B virus (HBV) infection. The HBV X protein (HBx) plays a central role in hepatocarcinogenesis by regulating transcription, signal transduction, epigenetic modification, and interactions with noncoding RNAs. This review summarizes current advances in HBx-mediated signaling pathways and mutation-specific functions, highlighting its potential as a prognostic biomarker and therapeutic target, and providing insights for future strategies in HCC treatment and HBV eradication. Activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), cAMP response element binding protein/activating transcription factor (CREB/ATF), and phosphatidylinositol 3′-kinase/AKT serine-threonine protein kinase family (PI3K/Akt) pathways by HBx promotes tumor proliferation, epithelial–mesenchymal transition, and immune evasion. Mutation- and truncation-specific variants of HBx, such as C1485T, C1653T, and K130M/V131I, further enhance oxidative stress, inflammatory signaling, and chemoresistance, contributing to poor prognosis. Emerging preclinical evidence indicates that natural compounds, including asiatic acid, sphondin, and rapamycin, can suppress HBx stability and transcriptional activity, offering novel antiviral and antitumor strategies. Understanding HBx-driven molecular mechanisms and mutation-specific effects may guide the development of precise diagnostic, prognostic, and therapeutic approaches for HBV-related HCC.