Viral Manipulation of Host Signaling Pathways by Hepatitis B Virus (HBV): Implications for Liver Disease Progression and Targeted Therapy

Abstract

Hepatitis B virus (HBV) infection remains a major global health burden and is strongly associated with chronic hepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The progression of HBV-associated liver disease is primarily mediated through complex interactions between viral proteins and host cellular signaling pathways rather than direct viral cytotoxicity alone. This article comprehensively investigates the molecular mechanisms by which HBV manipulates host signaling networks to establish persistent infection, evade immune responses, and promote liver disease progression. Particular emphasis was placed on the role of the HBx protein in regulating inflammatory, proliferative, apoptotic, fibrogenic, and oncogenic pathways. The study systematically evaluated HBV-induced dysregulation of key signaling cascades including NF-κB, PI3K/Akt/mTOR, JAK/STAT, MAPK/ERK, Wnt/β-catenin, and TGF-β pathways and their contribution to chronic inflammation, oxidative stress, fibrosis, immune dysfunction, and hepatocarcinogenesis. Result-oriented analysis demonstrated that HBV significantly suppresses innate and adaptive immune responses through inhibition of Toll-like receptor signaling, reduced interferon production, impaired natural killer cell activity, and induction of T-cell exhaustion via PD-1, CTLA-4, and TIM-3 upregulation. Persistent activation of inflammatory and survival pathways promoted hepatic stellate cell activation, extracellular matrix deposition, genomic instability, and malignant transformation. Therapeutic findings indicated that direct-acting antivirals effectively suppress viral replication but fail to eliminate covalently closed circular DNA (cccDNA). Emerging therapeutic strategies including host-targeting antivirals, immune checkpoint inhibitors, RNA interference, CRISPR/Cas gene editing, and epigenetic therapies demonstrated promising outcomes in restoring antiviral immunity, reducing fibrosis, and suppressing viral persistence. Overall, this study highlights the critical role of HBV-host signaling interactions in liver disease progression and emphasizes the importance of targeted molecular therapies for achieving functional cure and preventing HBV-associated hepatocellular carcinoma.