Zinc finger protein ZBTB7A suppresses hepatitis B virus replication by attenuating FXRα-mediated HBV transcription and lowering covalently closed circular DNA levels.

Chronic hepatitis B virus (HBV) infection remains a major global public health challenge, partly because of significant gaps in our understanding of its pathogenesis. Host factors play critical roles in regulating specific stages of the HBV life cycle, including replication. ZBTB7A, a member of the POK family of zinc-finger transcription factors, is involved in carcinogenesis and the modulation of certain viral infections. However, its role in HBV replication remains unclear, and this study aims to address this. We observed that ZBTB7A mRNA levels were higher in the immune-control phase than in the immune-tolerant phase and were inversely correlated with serum HBV DNA levels. ZBTB7A mRNA and protein levels were significantly downregulated in liver tissues from patients with chronic HBV infection, as well as in HBV-expressing hepatoma cells and primary human hepatocytes (PHHs). ZBTB7A overexpression markedly reduced HBV transcription and replication in HBV-infected hepatoma cells, PHHs, and an HBV-persistent mouse model. Mechanistically, ZBTB7A significantly repressed HBV transcription by suppressing viral core promoter activity, which in turn was achieved by reducing FXRα expression. ZBTB7A also physically interacted with FXRα, contributing to the inhibition of HBV transcription. In addition, ZBTB7A upregulated APOBEC3A expression, a mechanism that likely contributed to the observed reduction in covalently closed circular DNA (cccDNA) levels. Collectively, our data demonstrate that ZBTB7A suppresses HBV transcription and replication by diminishing both the amount and transcriptional activity of cccDNA. These findings suggest that ZBTB7A is a promising novel host-directed target for therapeutic intervention against HBV infection.