OBJECTIVETo explore the effects of mothers against decapentaplegic homolog family member 4 (Smad4) deletion on inflammation and fibrogenesis in nonalcoholic steatohepatitis (NASH). METHODSBiopsied liver samples from NASH patients and normal liver tissue samples from patients who had received liver resection for trauma were collected. Smad4(Co/Co) and wild-type (WT) mice were used to construct the NASH model using a high-fat diet (HFD) or methionine- and choline-deficient diet (MCD). HE staining and TUNEL assay were used to observe the pathological changes and cell apoptosis, respectively. Quantitative real-time polymerase chain reaction was used to detect the expression of inflammatory, fibrogenesis and apoptosis-related genes, and immunohistochemistry to determine the protein expression of SMAD4, MCP-1 and -SMA. RESULTSSMAD4 protein expression significantly increased in NASH patients than in the control group. Compared with WT mice, HFD- and MCD-fed Smad4(Co/Co) mice showed decreased hepatic steatosis, inflammation, liver cell apoptosis and nonalcoholic fatty liver activity score, reduced plasma glucose, triglyceride, free fatty acids, alanine aminotransferase and aspartate aminotransferase levels but increased adiponectin. Moreover, Smad4(Co/Co) decreased the expression of inflammatory markers (TNF-, MCP-1, IFN-), fibrogenetic markers (COL1A1, -SMA and TGF-1), lipogenic (Srebp1c, Fas and Acc) and proapoptotic genes (Bax and caspase-3), but increased the expression of -oxidation (Ppar-, Cpt1 and Aco) and antiapoptotic genes (Bcl-2). CONCLUSIONSmad4 deletion may inhibit lipogenesis, stimulate -oxidation, improve lipid metabolism and liver function, alleviate inflammation and fibrosis, and reduce cell apoptosis in NASH.