<span class="paragraphSection"><div class="boxTitle">Abstract</div>Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) constitutes a viral persistence reservoir that sustains chronic infection. Although the DNA damage response (DDR) facilitates cccDNA biogenesis, its role in regulating cccDNA stability remains unclear. By intersecting published cccDNA-associated proteomic datasets with known DDR-related host factors, we identified heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) as a novel restriction factor that binds cccDNA and suppresses HBV replication by promoting cccDNA degradation. Mechanistically, hnRNPA2B1 interacted with the G-quadruplex (G4) structure of cccDNA, with preference for G4-1, G4-7, and G4-10, and leads to the recruitment of the cytidine deaminase APOBEC3B by its prion-like domain (PrLD), thereby inducing C&gt;T and G&gt;A hypermutations and initiating cccDNA decay. Notably, HBV counteracts this defense mechanism through HBx-mediated hnRNPA2B1 polyubiquitination and proteasomal degradation, revealing a viral evasion strategy that perpetuates cccDNA persistence. These findings reveal a G4-dependent surveillance axis wherein hnRNPA2B1 directs APOBEC3B-mediated cytidine deamination to destabilize cccDNA while identifying HBx-induced hnRNPA2B1 ubiquitination as a viral countermeasure. This mechanistic duality not only elucidates a critical virus-host interaction governing cccDNA persistence but also provides a promising therapeutic target for the treatment of HBV infection.</span>