Luteolin Inhibits Hepatitis B Virus Replication through Extracellular Signal-Regulated Kinase-Mediated Down-Regulation of Hepatocyte Nuclear Factor 4α Expression

Whether luteolin inhibits HBV replication has not been validated and the underlying mechanism of which has never been elucidated. In this study, we show that luteolin reduces HBV DNA replication in HepG2.2.15 cells. Luteolin effectively inhibited the expression of hepatocyte nuclear factor 4α (HNF4α) and its binding to the HBV promoters in HepG2.2.15 cells. While the extracellular signal-regulated kinase (ERK) was activated by luteolin, inhibition of ERK abolished luteolin-induced HNF4α suppression. Consistently, blocking ERK attenuated the anti-HBV activity of luteolin. In a HBV replication mouse model, luteolin decreased the levels of HBsAg, HBeAg, HBV DNA replication intermediates, and the HBsAg and HBcAg expression. Taken together, our results validated the anti-HBV activity of luteolin in both in vitro and in vivo studies and established a signaling cascade consisting of ERK and HNF4α for inhibition of HBV replication by luteolin, which may be exploited for clinical application of luteolin for anti-HBV therapy.