Metabolic-epigenetic regulation of the HBV cccDNA reservoir: pathways underpinning viral persistence

Chronic hepatitis B virus (HBV) infection remains a global public health burden, and functional cure represents the primary goal of clinical management. The nuclear covalently closed circular DNA (cccDNA) minichromosome stably maintained in infected hepatocytes constitutes the major barrier to HBV cure. Clinically, functional cure is defined as sustained hepatitis B surface antigen (HBsAg) seroclearance with undetectable serum HBV DNA after finite treatment, a definition that does not require complete cccDNA elimination. At the molecular level, functional cure is thought to be associated with stable transcriptional silencing of cccDNA and integrated HBV DNA, a state biologically distinct from physical cccDNA depletion. Accumulating data demonstrate that the persistence and transcriptional homeostasis of the cccDNA reservoir are controlled by viral proteins and dynamically shaped by host metabolic signaling and epigenetic remodeling. Here, we first outline key steps of the HBV life cycle to establish the mechanistic context for cccDNA formation and replenishment, and then focus our synthesis on the integrated host metabolic-epigenetic network that governs cccDNA establishment, transcriptional activity, stability, and clearance. We dissect how central carbon metabolites, bile acid signaling, histone post-translational modifications, and immune cytokines converge to modulate cccDNA reservoir homeostasis, and critically evaluate the strength of evidence supporting their physiological relevance in the chronically infected human liver. We also discuss mechanisms of HBV immune evasion, including hepatitis B virus X protein (HBx)-driven epigenetic reprogramming and subviral particle-associated immune tolerance. We summarize preclinical and clinical therapeutic strategies targeting the metabolic-epigenetic microenvironment, viral assembly, antigen secretion, and cccDNA modulation to achieve a functional cure for HBV infection. Finally, we outline key unresolved challenges in the field, including the undefined in vivo cccDNA turnover kinetics, the poorly characterized physiological relevance of cell-to-cell transmission, the inherent limitations of gene-editing technologies, and the urgent need for specific non-invasive biomarkers reflecting intrahepatic cccDNA activity.