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Mitochondrial division inhibitor 1 (Mdivi1) is a potential inhibitor of dynamin\u2010related protein (Drp1) and mitochondrial fission. However, the therapeutic effect of Mdivi1 against NASH and its underlying molecular mechanisms remain unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we established mouse models of NASH by inducing high\u2010fat\/high\u2010cholesterol (HFHC) or methionine\u2010 and choline\u2010deficient (MCD) diets and treated the animals with 5\u00a0mg\/kg\/day Mdivi1 or placebo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Treatment with Mdivi1 significantly alleviated diet\u2010induced fatty liver phenotypes, including increased liver weight\/body weight ratio, insulin resistance, hepatic lipid accumulation, steatohepatitis, and liver injury. Furthermore, Mdivi1 treatment suppressed HFHC or MCD diet\u2010induced changes in the expression of genes related to lipid metabolism and inflammatory cytokines. Additionally, Mdivi1 reduced macrophage infiltration in the injured liver and promoted polarization of macrophages towards the M1 phenotype. At the molecular level, Mdivi1 attenuated mitochondrial fission by reducing Drp1 activation and expression, thereby decreasing mitochondrial reactive oxygen species accumulation and mitochondrial DNA damage. Moreover, Mdivi1\u2010treated mice exhibited elevated levels of phosphorylated\u2010c\u2010Jun N\u2010terminal kinase (p\u2010JNK), mitochondrial fission factor (MFF), cleaved caspase 3 protein, and TUNEL\u2010positive cell expression in the liver, suggesting that Mdivi1 might ameliorate mitochondrial dysfunction and reduce hepatocyte apoptosis by inhibiting the JNK\/MFF pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Collectively, Mdivi1 protected against diet\u2010induced NASH by restoring mitochondrial homeostasis and function, potentially through its inhibitory effect on the JNK\/MFF pathway. Consequently, further investigation of Mdivi1 as a promising drug for NASH treatment is warranted.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jgh.16372","type":"journal-article","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T00:53:50Z","timestamp":1697417630000},"page":"2215-2227","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Mdivi1 ameliorates mitochondrial dysfunction in non\u2010alcoholic steatohepatitis by inhibiting JNK\/MFF signaling"],"prefix":"10.1111","volume":"38","author":[{"given":"Ying","family":"Quan","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center Guangzhou First People's Hospital  Guangzhou China"},{"name":"Department of Gastroenterology and Hepatology, Second Affiliated Hospital, School of Medicine South China University of Technology  Guangzhou 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