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The metabolic reprogramming of HSCs plays a major role in this process to meet the high energy demands of myofibroblastic HSCs with multiple functions, such as extracellular matrix synthesis, migration, and proliferation. AMP-activated protein kinase (AMPK) is a gatekeeper of intracellular energy homeostasis, but its role in the activation of HSCs and the progression of liver fibrosis remains unclear. Here, we found that the phosphorylation of AMPK in HSCs was upregulated in liver tissues from metabolic dysfunction-associated steatohepatitis patients and from mice treated with carbon tetrachloride (CCl4) or bile duct ligation (BDL). HSC-specific deletion of two catalytic \u03b1-subunits of AMPK attenuated liver fibrosis in the CCl4 or BDL mouse model. In vitro analysis demonstrated that AMPK promoted HSC activation upon various profibrogenic stimuli. The activation of AMPK\u03b1-deficient HSCs was impaired due to the decreased mitochondrial oxidative phosphorylation but restored after treatment with the mitophagy inducer rapamycin. Mechanistically, both the AMPK\u2013ULK1 and AMPK\u2013Raptor pathways contribute to the maintenance of the mitophagy pathway and mitochondrial quality. These findings provide direct evidence of the crucial role of AMPK\u2013mitophagy signaling in ensuring mitochondrial health and sufficient energy supply during HSC activation. In this study, AMPK was modulated in HSCs prior to activation, which is distinguished from previous investigations and thus provides new insights into the role of AMPK during distinct phases of HSC activation.<\/jats:p>","DOI":"10.1093\/jmcb\/mjaf030","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T11:49:12Z","timestamp":1756900152000},"source":"Crossref","is-referenced-by-count":10,"title":["AMPK maintains the activation of hepatic stellate cells through mitophagy-induced metabolic reprogramming"],"prefix":"10.1093","volume":"17","author":[{"given":"Hanmin","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 ,","place":["China"]},{"name":"Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery , Yantai 264117 ,","place":["China"]},{"name":"University of Chinese Academy 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of Chinese Materia Medica, Nanjing University of Chinese Medicine , Nanjing 210023 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanlin","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing 100049 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yikai","family":"Shao","sequence":"additional","affiliation":[{"name":"Center for Obesity and Hernia Surgery, Huashan Hospital of Fudan University , Shanghai 200040 ,","place":["China"]},{"name":"Department of General Surgery, Huashan Hospital of Fudan University , Shanghai 200040 ,","place":["China"]},{"name":"National Center for Neurological Disorders, Huashan Hospital of Fudan University , Shanghai 200040 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University , Shanghai 200040 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 ,","place":["China"]},{"name":"Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery , Yantai 264117 ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing 100049 ,","place":["China"]},{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Zhongshan 528400 ,","place":["China"]},{"name":"School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences , Hangzhou 310024 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