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

Abstract

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. This review aims to evaluate the role of HBx in HBV&#x2011;related HCC progression and to examine the therapeutic potential of natural products that directly target HBx and indirectly modulate HBx&#x2011;driven antiviral and oncogenic pathways. A comprehensive literature analysis was conducted focusing on studies published over the past decade, including <i>in vitro</i>, <i>in vivo</i>, and clinical evidence addressing HBx-mediated mechanisms and the pharmacological effects of bioactive natural products, including plant&#x2011;derived phytochemicals and non&#x2011;plant natural compounds. Accumulating evidence indicates that some natural products suppress HBV replication by reducing HBx expression, promoting HBx degradation, or limiting HBx&#x2011;dependent cccDNA transcription, whereas others primarily influence biological pathways associated with HBx&#x2011;driven hepatocarcinogenesis, including migration, invasion, fibrosis, metabolic reprogramming, and apoptosis resistance. 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.