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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 (ER\u03b1) binding affinity of BA and its estrogen-like agonist activity were subsequently verified through molecular docking assays, BA-ER\u03b1 affinity detection experiments, ER\u03b1 luciferase reporter gene assays, and qRT-PCR. ER\u03b1 knockdown (shRNA) and AMPK inhibition (Compound C and doxorubicin [Dox]) experiments revealed that the sequential activation of the ER\u03b1-LKB1-AMPK-HNF signaling axis is essential for the anti-HBV effects of BA. This study indicates that BA may trigger the ER\u03b1-AMPK\u03b1-HNF pathway to inhibit HBV replication, providing insights into its potential protective mechanisms against other viruses.<\/jats:p>","DOI":"10.1038\/s41401-024-01408-3","type":"journal-article","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T14:53:36Z","timestamp":1730300016000},"page":"653-661","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Sequential activation of ER\u03b1-AMPK\u03b1 signaling by the flavonoid baicalin down-regulates viral HNF-dependent HBV replication"],"prefix":"10.1038","volume":"46","author":[{"given":"Yi-jun","family":"Niu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-jie","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Ai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-ming","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-tong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-qi","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-yan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong-lian","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun-long","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,30]]},"reference":[{"key":"1408_CR1","doi-asserted-by":"crossref","first-page":"e362","DOI":"10.1016\/S1473-3099(24)00307-4","volume":"24","author":"T Burki","year":"2024","unstructured":"Burki T. 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