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This research examines the involvement of chaperone\u2010mediated autophagy (CMA) in NASH progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Hepatic CMA activity was analysed in NASH mice and patients. Lysosome\u2010associated membrane protein 2A (LAMP2A) was knocked down or overexpressed to assess the effects of hepatocyte\u2010specific CMA on NASH progression. Mice received a high\u2010fat diet or a methionine and choline\u2010deficient diet to induce NASH. Palmitic acid was employed to mimic lipotoxicity\u2010induced hepatocyte damage in vitro. The promoter activity of FOXM1 was evaluated via ChIP and dual\u2010luciferase reporter assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Hepatic CMA activity was substantially low in NASH mice and patients. LAMP2A knockdown resulted in hepatocyte\u2010specific CMA deficiency, which promoted fibrosis and hepatic inflammation in NASH mice. Both in vitro and in vivo, CMA deficiency also exacerbated hepatocyte damage and endoplasmic reticulum (ER) stress. Mechanistically, CMA deficiency in hepatocytes increased cholesterol accumulation by blocking the degradation of 3\u2010hydroxy\u20103\u2010methylglutaryl coenzyme A (HMGCR), a key cholesterol synthesis\u2010related enzyme, and the accumulated cholesterol subsequently induced ER stress and hepatocyte damage. The restoration of hepatocyte\u2010specific CMA activity effectively ameliorated diet\u2010induced NASH and ER stress in vivo and in vitro. FOXM1 directly bound to LAMP2A promoter and negatively regulated its transcription. The upregulation of FOXM1 expression impaired CMA and enhanced ER stress, which in turn increased FOXM1 expression, resulting in a vicious cycle and promoting NASH development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study highlights the significance of the FOXM1\/CMA\/ER stress axis in NASH progression and proposes novel therapeutic targets for NASH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Chaperone\u2010mediated autophagy (CMA) deficiency in hepatocytes promotes hepatic inflammation and fibrosis in mice with nonalcoholic steatohepatitis (NASH) by inducing cholesterol accumulation and endoplasmic reticulum (ER) stress.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Upregulated FOXM1 impairs CMA by suppressing the transcription of lysosome\u2010associated membrane protein 2A (LAMP2A), a rate\u2010limiting component of CMA.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>ER stress increases FOXM1 expression and cholesterol accumulation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>FOXM1\/CMA\/ER stress axis forms a vicious circle and promotes the development of NASH.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70202","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T23:25:13Z","timestamp":1739229913000},"source":"Crossref","is-referenced-by-count":8,"title":["Role of the FOXM1\/CMA\/ER stress axis in regulating the progression of nonalcoholic steatohepatitis"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7306-2489","authenticated-orcid":false,"given":"Shuoyi","family":"Ma","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cancer Biology Xijing Hospital of Digestive Diseases, The Fourth Military Medical University  Xi'an 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