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In this study, we demonstrated that baicalin, a major active component of the traditional Chinese medicine Scutellaria baicalensis, was able to inhibit the activation of hepatic stellate cells and attenuate liver fibrosis in various mouse models. In order to elucidate the molecular basis of its antifibrotic effects, we designed a novel baicalin photo-cross-linking probe and applied a quantitative chemoproteomic strategy based on dimethyl labeling to profile baicalin-interacting proteins. Aided by systematic gene knockouts of these potential baicalin interactors, we identified STAT3 as a key target in mediating the antifibrotic function of baicalin. Mechanistically, baicalin primarily binds to the N-terminal domain of STAT3, inhibits its interaction with JAK2 and thereby suppresses STAT3 phosphorylation. Our findings reveal the molecular mechanism of the antifibrotic effects of baicalin and provide a theoretical basis for the design of new antifibrotic drugs based on the structure of baicalin.<\/jats:p>","DOI":"10.1093\/nsr\/nwag093","type":"journal-article","created":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T12:44:07Z","timestamp":1771073047000},"source":"Crossref","is-referenced-by-count":7,"title":["Chemoproteomics identifies STAT3 as a key target of baicalin in ameliorating liver fibrosis"],"prefix":"10.1093","volume":"13","author":[{"given":"Shouli","family":"Yuan","sequence":"first","affiliation":[{"name":"Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University , Beijing 100871 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Fei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Synthetic and Functional Biomolecules Center, Beijing National Laboratory for 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Chengdu 610094 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifan","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences , Beijing 100700 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengzhang","family":"Wang","sequence":"additional","affiliation":[{"name":"Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University , Beijing 100871 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anqi","family":"Yu","sequence":"additional","affiliation":[{"name":"Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University , Beijing 100871 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