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RNA\u2010seq and lipidomic analyses were conducted to depict the metabolic landscape, and CUT&amp;Tag combined with chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this work, we observed a notable increase in <jats:italic>DDX17<\/jats:italic> expression in the livers of patients with NASH and in murine models of NASH induced by HFD or MCD. After introducing lentiviruses into hepatocyte L02 for <jats:italic>DDX17<\/jats:italic> knockdown or overexpression, we found that lipid accumulation induced by palmitic acid\/oleic acid (PAOA) in L02 cells was noticeably weakened by <jats:italic>DDX17<\/jats:italic> knockdown but augmented by <jats:italic>DDX17<\/jats:italic> overexpression. Furthermore, hepatocyte\u2010specific <jats:italic>DDX17<\/jats:italic> knockout significantly alleviated hepatic steatosis, inflammatory response and fibrosis in mice after the administration of MCD and HFD. Mechanistically, our analysis of RNA\u2010seq and CUT&amp;Tag results combined with ChIP and luciferase reporter assays indicated that <jats:italic>DDX17<\/jats:italic> transcriptionally represses <jats:italic>Cyp2c29<\/jats:italic> gene expression by cooperating with CCCTC binding factor (<jats:italic>CTCF<\/jats:italic>) and DEAD\u2010Box Helicase 5 (<jats:italic>DDX5<\/jats:italic>). Using absolute quantitative lipidomics analysis, we identified a hepatocyte\u2010specific <jats:italic>DDX17<\/jats:italic> deficiency that decreased lipid accumulation and altered lipid composition in the livers of mice after MCD administration. Based on the RNA\u2010seq analysis, our findings suggest that <jats:italic>DDX17<\/jats:italic> could potentially have an impact on the modulation of lipid metabolism and the activation of M1 macrophages in murine NASH models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results imply that <jats:italic>DDX17<\/jats:italic> is involved in NASH development by promoting lipid accumulation in hepatocytes, inducing the activation of M1 macrophages, subsequent inflammatory responses and fibrosis through the transcriptional repression of <jats:italic>Cyp2c29<\/jats:italic> in mice. Therefore, <jats:italic>DDX17<\/jats:italic> holds promise as a potential drug target for the treatment of NASH.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1529","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T07:39:57Z","timestamp":1706859597000},"source":"Crossref","is-referenced-by-count":14,"title":["DEAD\u2010Box Helicase 17 exacerbates non\u2010alcoholic steatohepatitis via transcriptional repression of cyp2c29, inducing hepatic lipid metabolism disorder and eliciting the activation of M1 macrophages"],"prefix":"10.1002","volume":"14","author":[{"given":"Deng","family":"Ning","sequence":"first","affiliation":[{"name":"Department of Hepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan China"},{"name":"Hubei Key Laboratory of Hepato\u2010Pancreato\u2010Biliary Diseases  Wuhan China"},{"name":"Department of Hepatobiliary Surgery Union Hospital Tongji Medical College Huazhong 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