摘要Baicalin(BA),a natural component found in many traditional Chinese medicines,exerts protective effects against several viruses.Although our previous studies have revealed that the anti-hepatitis B virus(anti-HBV)activity of BA depends on hepatocyte nuclear factor(HNF)signaling,the specific mechanisms remain unclear.The present study explored the potential signaling mechanisms involved in BA-mediated HBV suppression.Transcriptomic analysis suggested that BA significantly modulates the estrogen receptor(ER)and AMPK signaling pathways in HepG2 cells.The ER alpha(ERα)binding affinity of BA and its estrogen-like agonist activity were subsequently verified through molecular docking assays,BA-ERα affinity detection experiments,ERα luciferase reporter gene assays,and qRT-PCR.ERα knockdown(shRNA)and AMPK inhibition(Compound C and doxorubicin[Dox])experiments revealed that the sequential activation of the ERα-LKB1-AMPK-HNF signaling axis is essential for the anti-HBV effects of BA.This study indicates that BA may trigger the ERα-AMPKα-HNF pathway to inhibit HBV replication,providing insights into its potential protective mechanisms against other viruses.