Astragalin inhibits hepatitis B virus through functional reconstitution of CD8+ T cells and a direct effect on HBV control.

Persistent HBV infection promotes hepatic lipid accumulation, a feature linked to immune dysfunction. We found cytotoxic T lymphocytes (CD8+ T cells) from chronic HBV infection (CHB) patients exhibited elevated lipid peroxidation in response to hepatic lipids accumulation. And lipid peroxidation drives CD8+ T cell dysfunction. Astragalin (AG), a natural active compound from Chinese herbs, reduced lipid peroxidation. Mechanically, AG upregulated Glutathione peroxidase 4 (GPX4) expression, protecting CD8+ T cells against membrane lipid peroxidation and reversing their exhaustion during chronic HBV infection. Importantly, AG significantly reduced circulating serum HBsAg and HBV DNA levels in HBV-carrier mice. Furthermore, AG directly reduced HBsAg, HBeAg and HBV RNA levels in HepG2.2.15 cells and significantly induced expression of the interferon-inducible antiviral protein myxovirus resistance protein A (MxA). In conclusion, AG exhibits dual anti-HBV activity by enhancing CD8+ T cell antiviral function and directly suppressing HBV replication, holding promise as a potential candidate for the treatment of chronic HBV infection.