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This study aimed to clarify the role and mechanism of micheliolide in treating hepatic fibrosis. Methods: The efficacy of MCL was evaluated in a mouse model of CCl4-induced hepatic fibrosis. LX-2 cells were subjected to MCL treatment, and subsequent changes in fibrosis markers, autophagy, and the MEK\/ERK pathway were analyzed using transcriptomics and Western blotting. The interaction between MCL and TrxR1 or TrxR2 were validated using cellular thermal shift assays (CETSA) and drug affinity responsive target stability (DARTS) assays. Results: Our findings indicated that MCL significantly alleviated CCl4-induced hepatic fibrosis, improved liver function, and downregulated the expression of fibrosis markers. Additionally, MCL significantly inhibited LX-2 cell activation by suppressing cell proliferation, extracellular matrix (ECM) production, and autophagy, while activating the MEK\/ERK pathway. Moreover, MCL elevated intracellular and mitochondrial reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential, and altered mitochondrial morphology. The ROS scavenger N-acetylcysteine (NAC) attenuated MCL-induced MEK\/ERK pathway activation and increased collagen type I alpha 1 (COL1A1) and fibronectin (FN) expression. Further analysis confirmed that MCL directly interacts with TrxR1 and TrxR2, leading to the inhibition of their enzymatic activities and the induction of ROS generation. Ultimately, MCL attenuated the fibrotic process and autophagic flux in LX-2 cells. Conclusions: The findings of our study confirmed that MCL has the potential to alleviate hepatic fibrosis, thereby introducing a novel candidate drug and therapeutic strategy for management of this condition.<\/jats:p>","DOI":"10.3390\/ph18030287","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T11:03:37Z","timestamp":1740049417000},"page":"287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Micheliolide Alleviates Hepatic Fibrosis by Inhibiting Autophagy in Hepatic Stellate Cells via the TrxR1\/2-Mediated ROS\/MEK\/ERK Pathway"],"prefix":"10.3390","volume":"18","author":[{"given":"Yi","family":"Liu","sequence":"first","affiliation":[{"name":"Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Yao","sequence":"additional","affiliation":[{"name":"College of Traditional Chinese Medicine, Chongqing University of Chinese Medicine, Chongqing 402760, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunheng","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ailing","family":"Liang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honglin","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Lei","sequence":"additional","affiliation":[{"name":"Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenfu","family":"Cao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiwei","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China"},{"name":"College of Traditional Chinese Medicine, Chongqing University of Chinese Medicine, Chongqing 402760, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.jhep.2018.09.014","article-title":"Burden of liver diseases in the world","volume":"70","author":"Asrani","year":"2019","journal-title":"J. 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