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Previous studies have confirmed that the estrogen receptor ER\u03b1 inhibits HBV transcription. However, reports on combined treatment with ER\u03b1 and peg IFN\u03b1-2b for HBV infection are limited. Hepatocyte RNA-seq analysis revealed that both ER\u03b1 elevation and IFN\u03b1 stimulation can lead to increased expression of GBP1. GBP1 has been reported to inhibit several bacteria and HCV, but evidence of its effect on HBV infection is insufficient.We systematically investigated the roles of ER\u03b1, peg IFN\u03b1-2b, and GBP1 in modulating HBV infection in an HBV-infected HepG2-NTCP cell model. Molecular dynamics simulation and molecular docking methods were employed to analyze the stability and interaction sites of the ER\u03b1 and GBP1 complex. Finally, we examined the RNA and protein levels of GBP1 and ER\u03b1 in the peripheral blood of CHB patients treated with peg IFN\u03b1-2b.GBP1 was induced by costimulation with ER\u03b1 and peg IFN\u03b1-2b. The combination of ER\u03b1 and peg IFN\u03b1-2b enhanced the inhibition of HBV replication, which might be achieved by promoting GBP1 expression and altering its cellular distribution. GBP1 was highly expressed in the PBMCs and liver tissues of CHB patients and was specifically positively correlated with ER\u03b1. Interestingly, GBP1 was enriched in the NOD-like signalling pathway, which activates the host immune response.Our study demonstrated that the combination of ER\u03b1 and peg IFN\u03b1-2b exerts antiviral effects by mediating the high expression of GBP1. These findings reveal the associations among ER\u03b1, peg IFN\u03b1-2b, and innate antiviral immunity, which target GBP1.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1698786","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T05:22:04Z","timestamp":1768540924000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Combined therapy with the estrogen receptor ER\u03b1 and IFN\u03b1-2b suppresses HBV replication by inducing GBP1 expression"],"prefix":"10.3389","volume":"16","author":[{"given":"Yadi","family":"Li","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Laboratory for Clinical Medicine, Beijing You\u2019an Hospital Affiliated with Capital Medical University","place":["Beijing, China"]},{"name":"Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, The First Affiliated Hospital of Chongqing 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