SOX6 is a novel host factor that promotes hepatitis B virus replication by enhancing the transcriptional activity of enhancer I

Chronic hepatitis B virus (HBV) infection is a major global health problem. Currently, existing antiviral drugs are difficult to achieve a functional cure for chronic hepatitis B (CHB). Therefore, it is necessary to develop new antiviral targets, especially those that can directly target HBV covalently closed circular DNA (cccDNA) in hepatocytes. Here, we identified a conserved SOX6 binding site in the enhancer I (ENI) region of the HBV genome, and found that SOX6 promotes the replication of multiple genotypes HBV through its HMG domain. Mechanistically, SOX6 binds to the conserved binding site located in the HBV ENI region through its HMG domain, thereby promoting HBV replication by enhancing the transcriptional activity of ENI. Moreover, cisplatin and doxorubicin not only promote HBV replication but also promote SOX6 expression. Knocking down the expression of endogenous SOX6 or mutating the SOX6 binding site in the HBV ENI region significantly weakens the direct promoting effect of cisplatin and doxorubicin on HBV replication. In summary, SOX6 promotes HBV replication by enhancing the transcriptional activity of HBV ENI through its HMG domain, suggesting that it can serve as a potential target for regulating HBV cccDNA transcription. In addition, SOX6 participates in the direct promotion of HBV replication by cisplatin and doxorubicin, providing new insights into the molecular mechanisms of tumor chemotherapy related HBV reactivation (HBVr) and potential targets for the prevention of HBVr during tumor chemotherapy.