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Class A capsid assembly modulators (CAM\u2010As) emerge as a promising treatment option. CAM\u2010As not only directly disrupt the normal assembly of capsids, but some of which have also been reported to activate the innate immune response in animal models with unclear mechanisms. GLS4 is one of CAM\u2010As with great potential. In this study, we investigate its capacity to activate immune response both in vitro and in vivo, as well as the underlying mechanisms involved. GLS4 activates the RIG\u2010I\u2010mediated interferon signaling pathway in both HBV\u2010expressing hepatocellular carcinoma cell lines and HBV carrier mouse models, as indicated by RNA\u2010seq. Besides, combination treatment with GLS4 and ritonavir elevates the frequencies of both peripheral blood IFN\u03b3\u2009+\u2009NK cells and liver\u2010resident IFN\u03b3\u2009+\u2009CD8+ T cells in the pAAV\/HBV1.2 hydrodynamic injection (HDI) model. In conclusion, our study reveals a previously unknown mechanism by which GLS4 activates the interferon signaling pathway in HBV\u2010expressing hepatocytes. Furthermore, GLS4 partially restores innate and adaptive immunity in vivo. This signifies a potentially effective strategy for achieving a functional cure for HBV infection.<\/jats:p>","DOI":"10.1002\/jmv.70777","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T11:27:10Z","timestamp":1767353230000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["GLS4 Induces the Interferon Signaling Pathway During Hepatitis B Virus (HBV) Infection"],"prefix":"10.1002","volume":"98","author":[{"given":"Lingzhu","family":"Zhao","sequence":"first","affiliation":[{"name":"State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine Zhejiang University Hangzhou Zhejiang 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