Current treatment methods for hepatitis B are mainly antiviral drug therapy and immunotherapy, in which antiviral drugs are mainly nucleoside analogue and interferon. They can significantly reduce the viral load but rarely achieve hepatitis B surface antigen (HBsAg) loss. 3,5,6,7,3′,4′-Hexamethoxyflavone was screened out from a small molecule compound library for its lower cytotoxic effect and greater HBsAg inhibition activity. Meanwhile, we further performed experiments in HepG2.2.15, HepG2-NTCP cells, PHHs and HBV transgenic mouse model to evaluate the anti-HBV effects of 3,5,6,7,3′,4′-Hexamethoxyflavone. Our study found that 3,5,6,7,3′,4′-Hexamethoxyflavone can significantly reduce the level of HBV RNAs, HBV DNA and HBsAg, in addition, the activity of four HBV promoters and the ratio of total RNAs/cccDNA and 3.5 kb RNA/cccDNA were decreased by 3,5,6,7,3′,4′-Hexamethoxyflavone. Mechanistically, we found HNF3α plays important roles in Hex mediated HBV transcription inhibition. Our study indicated Hex was a potential anti-HBV therapeutic drug.
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