Hepatitis B virus X protein-targeted therapeutic strategies toward a functional cure for chronic hepatitis B infection: A review

Background: Chronic hepatitis B (CHB) remains a major global health challenge, with persistent covalently closed circular DNA (cccDNA) and viral integration leading to lifelong infection, cirrhosis, and hepatocellular carcinoma (HCC). Current antiviral therapies suppress replication but rarely achieve a functional cure. The multifunctional hepatitis B virus (HBV) X (HBx) protein is well known to sustain viral replication, impair host immune responses, and promote hepatocarcinogenesis, which makes it an attractive therapeutic target. Aim: This review synthesizes current literature supporting HBx as a promising therapeutic target to achieve a functional cure of CHB. Conclusion: HBx is a high-value therapeutic target with potential to accelerate progress toward a functional cure. Destabilization or downregulation of HBx would not only attenuate its oncogenic signaling but also limit relapse after treatment discontinuation and diminish the cccDNA reservoir and viral antigen load. Relevance for patients: Multitargeted treatment regimens incorporating HBx-directed therapies hold the potential to achieve durable viral suppression and a functional cure, and to reduce the risk of HCC. The combined strategies could transform the long-term management and outcomes for patients with CHB.