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As a newly discovered programmed cell death mode, the regulatory mechanism of ferroptosis in the clearance of activated HSCs has not been fully elucidated. In the present study, we reported that the induction of ferroptosis in activated HSCs was required for dihydroartemisinin (DHA) to alleviate hepatic fibrosis. Treatment with DHA could improve the damage of hepatic fibrosis in vivo and inhibit the activation of HSCs in vitro. Interestingly, DHA treatment could trigger ferroptosis to eliminate activated HSCs characterized by iron overload, lipid ROS accumulation, glutathione depletion, and lipid peroxidation. Specific ferroptosis inhibitors ferrostatin\u20101 and liproxstatin\u20101 could impair DHA\u2010induced ferroptosis and also damage DHA\u2010mediated the inhibition of activated HSCs. Importantly, autophagy activation may be closely related to DHA\u2010induced ferroptosis. ATG5 siRNA could prevent DHA\u2010mediated autophagy activation and ferroptosis induction, whereas ATG5 plasmid could promote the effect of DHA on autophagy and ferroptosis. Of note, the upregulation of nuclear receptor coactivator 4 (NCOA4) may play a critical role in the molecular mechanism. NCOA4 siRNA could impair DHA\u2010induced ferroptosis, whereas NCOA4 plasmid could enhance the promoting effect of DHA on ferroptosis. Overall, our study revealed the potential mechanism of DHA against hepatic fibrosis and showed that ferroptosis could be a new way to eliminate activated HSCs.<\/jats:p>","DOI":"10.1002\/biof.1764","type":"journal-article","created":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T14:50:07Z","timestamp":1623768607000},"page":"801-818","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Dihydroartemisinin alleviates hepatic fibrosis through inducing ferroptosis in hepatic stellate cells"],"prefix":"10.1002","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6506-648X","authenticated-orcid":false,"given":"Zili","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Pharmacy, Nanjing University of Chinese Medicine  Nanjing China"},{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica Nanjing University of Chinese 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