Deoxycholic Acid Promotes Persistent Low‐Level Viremia in Chronic Hepatitis B via Enhancing HBV Particle Formation

BACKGROUND: Low-level viremia (LLV) during antiviral therapy predicts poor outcomes in chronic hepatitis B (CHB). Although bile acids (BAs) regulate HBV transcription, their role in LLV remains unclear. This study aimed to determine whether specific BAs affect antiviral efficacy and to identify potential therapeutic targets. METHODS: We analyzed 111 CHB patients, including LLV and lower detection limit (LDL) groups. Serum BAs were profiled by mass spectrometry. Propensity score matching (PSM), correlation, and ROC analyses evaluated the association between BAs and HBV DNA. In vitro, deoxycholic acid (DCA) was tested in HBV-producing HepG2.2.15 and HBV-infected HepG2-NTCP cells. In vivo, HBV-transgenic (HBV-Tg) mice were used to assess hepatic DCA and HBV DNA correlation. Treatments included entecavir (ETV), antibiotics, and DCA supplementation. Molecular docking and mutagenesis were conducted to explore DCA-HBV surface protein (HBs) interactions. RESULTS: After PSM, LLV patients had elevated DCA, LCA, and TUDCA levels, which correlated with HBV DNA. DCA modestly predicted LLV by ROC analysis. In vitro, DCA promoted HBV Dane particle secretion and infection without altering viral protein expression. In HBV-Tg mice, hepatic DCA correlated positively with HBV DNA. ETV and antibiotics reduced DCA and HBV DNA, whereas DCA supplementation reversed these effects. Mechanistically, DCA bound to LXXLL motifs in the HBs transmembrane domains, particularly TM2. TM2 mutations disrupted DCA binding, HBs-HBc interaction, and Dane particle formation. CONCLUSION: Elevated DCA promotes viral persistence by enhancing Dane particle formation and stabilizing HBs-HBc interactions, contributing to LLV during treatment. Modulating BA metabolism may offer new strategies to improve CHB therapy.