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However, how mitochondria regulate NASH progression remains largely unknown. Our previous findings demonstrate that mitochondrial general control of amino acid synthesis 5 like 1 (GCN5L1) is associated with mitochondrial metabolism. Nevertheless, the roles of GCN5L1 in NASH are unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims and methods<\/jats:title><jats:p>The GCN5L1 expression was detected in the fatty livers of NASH patients and animals. Hepatocyte\u2010specific GCN5L1 deficiency or overexpression mice were used to induce NASH models by feeding with a high\u2010fat\/high\u2010cholesterol or methionine\u2010choline deficient diet. The molecular mechanisms underlying GCN5L1\u2010regulated NASH were further explored and verified in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results and conclusions<\/jats:title><jats:p>GCN5L1 expression was increased in NASH patients. Upregulated GCN5L1 level was also illustrated in NASH mice. Mice with hepatocyte\u2010specific GCN5L1 conditional knockout improved the inflammatory response compared to GCN5L1<jats:sup>flox\/flox<\/jats:sup> mice. However, overexpression of mitochondrial GCN5L1 augmented the inflammatory response. Mechanically, GCN5L1 acetylated CypD and enhanced its binding with ATP5B, which induced the opening of mitochondrial permeability transition pores and the release of mitochondrial ROS into the cytoplasm. The increased ROS promoted ferroptosis of hepatocytes and induced accumulation of high mobility group box 1 in the microenvironment, which recruited neutrophils and induced the generation of neutrophil extracellular traps (NETs). NETs block impaired GCN5L1\u2010induced NASH progression. Furthermore, the upregulation of GCN5L1 in NASH was contributed by lipid overload\u2010induced endoplasmic reticulum stress. Together, mitochondrial GCN5L1 has a vital function in promoting NASH progression by regulating oxidative metabolism and the hepatic inflammatory microenvironment. Thus, GCN5L1 might be a potential intervention target in NASH treatment.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1325","type":"journal-article","created":{"date-parts":[[2023,7,7]],"date-time":"2023-07-07T05:50:15Z","timestamp":1688709015000},"source":"Crossref","is-referenced-by-count":26,"title":["Mitochondrial general control of amino acid synthesis 5 like 1 promotes nonalcoholic steatohepatitis development through ferroptosis\u2010induced formation of neutrophil extracellular traps"],"prefix":"10.1002","volume":"13","author":[{"given":"Tingting","family":"Lv","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Shandong Provincial Hospital Affiliated to Shandong First Medical University Jinan China"},{"name":"Department of Cancer Center Shandong Provincial Hospital Affiliated to Shandong First Medical University Jinan 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