Natural products targeting hepatitis B virus X protein and HBx-associated pathways in HBV-related hepatocellular carcinoma: mechanisms and therapeutic potential

CONTEXT: Hepatocellular carcinoma (HCC), largely driven by chronic hepatitis B virus (HBV) infection, remains a major global health challenge with limited curative options in advanced stages. The hepatitis B virus X protein (HBx) is a multifunctional viral oncoprotein that plays a central role in HBV persistence and hepatocarcinogenesis by disrupting transcriptional regulation, DNA repair, apoptosis, and immune responses. OBJECTIVE: This review aims to evaluate the role of HBx in HBV‑related HCC progression and to examine the therapeutic potential of natural products that directly target HBx and indirectly modulate HBx‑driven antiviral and oncogenic pathways. RESULTS: Accumulating evidence indicates that some natural products suppress HBV replication by reducing HBx expression, promoting HBx degradation, or limiting HBx‑dependent cccDNA transcription, whereas others primarily influence biological pathways associated with HBx‑driven hepatocarcinogenesis, including migration, invasion, fibrosis, metabolic reprogramming, and apoptosis resistance. CONCLUSION: Natural products represent a promising multi-target therapeutic strategy for HBV-related HCC by intervening in HBx-driven oncogenic processes. Future studies should focus on mechanistic validation, standardization of bioactive compounds, and well-designed clinical trials to support their translational application as adjunctive or alternative therapies.