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Macrophages play critical roles in initiating and maintaining NASH\u2010induced liver inflammation and fibrosis. However, the underlying molecular mechanism of macrophage chaperone\u2010mediated autophagy (CMA) in NASH remains unclear. We aimed to investigate the effects of macrophage\u2010specific CMA on liver inflammation and identify a potential therapeutic target for NASH treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The CMA function of liver macrophages was detected using Western blot, quantitative reverse transcription\u2010polymerase chain reaction (RT\u2010qPCR) and flow cytometry. By constructing myeloid\u2010specific CMA deficiency mice, we evaluated the effects of deficient CMA of macrophages on monocyte recruitment, liver injury, steatosis and fibrosis in NASH mice. A label\u2010free mass spectrometry was utilized to screen the substrates of CMA in macrophages and their mutual interactions. The association between CMA and its substrate was further examined by immunoprecipitation, Western blot and RT\u2010qPCR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A typical hallmark in murine NASH models was impaired CMA function in hepatic macrophages. Monocyte\u2010derived macrophages (MDM) were the dominant macrophage population in NASH, and CMA function was impaired in MDM. CMA dysfunction aggravated liver\u2010targeted recruitment of monocyte and promoted steatosis and fibrosis. Mechanistically, Nup85 functions as a substrate for CMA and its degradation was inhibited in CMA\u2010deficient macrophages. Inhibition of Nup85 attenuated the steatosis and monocyte recruitment caused by CMA deficiency in NASH mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We proposed that the impaired CMA\u2010induced Nup85 degradation aggravated monocyte recruitment, promoting liver inflammation and disease progression of NASH.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15547","type":"journal-article","created":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T15:25:50Z","timestamp":1678721150000},"page":"1021-1034","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Deficient <scp>chaperone\u2010mediated<\/scp> autophagy in macrophage aggravates inflammation of nonalcoholic steatohepatitis by targeting Nup85"],"prefix":"10.1111","volume":"43","author":[{"given":"Miao","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cancer biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si Y","family":"Tian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7306-2489","authenticated-orcid":false,"given":"Shuo Y","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao H","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guan Y","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia H","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Su","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang F","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi N","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Medical University  Xi'an 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