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Accumulating evidence suggests that vitamin D (VD) has a therapeutic effect on non-alcoholic fatty liver disease (NAFLD). Pyroptosis and gut microbiota have been recognized as critical factors of the progression of NAFLD. However, the effect of VD on the pyroptosis and gut microbiota in NAFLD remains inconclusive. Herein, rats were fed high fat diet (HFD) for 12 weeks and concurrently treated with 5 μ g/kg 1,25(OH) 2 D 3 twice a week. BRL-3A cells were stimulated with 0.4 mmol/L palmitic acid (PA) and 1 μ g/ml lipopolysaccharide (LPS) for 16 h and treated with 10−6 mol/L 1,25(OH) 2 D 3. Effect of VD on the hepatic injury, lipid accumulation, activation of NLRP3 inflammasome and pyroptosis was determined in vivo and in vitro. Next, gasdermin D N -terminal (GSDMD-N) fragment was overexpressed in BRL-3A cells to investigate the role of pyroptosis in the therapeutic effect of VD on NAFLD. In addition, gut microbiota in NAFLD rats was also analyzed. Results showed that VD attenuated HFD-induced hepatic injury in vivo and PA-LPS-induced impairment of cell viability in vitro , and inhibited lipid accumulation, activation of NLRP3 inflammasome and pyroptosis in vivo and in vitro. GSDMD-N fragment overexpression suppressed the protective effect of VD on PA-LPS-induced activation of NLRP3 inflammasome, impairment of cell viability and lipid accumulation, indicating that VD might attenuate NAFLD through inhibiting pyroptosis. Additionally, VD also restored HFD-induced gut microbiota dysbiosis by increasing the relative abundance of Lactobacillus and reducing that of Acetatifactor , Oscillibacter and Flavonifractor. This study provides a novel mechanism underlying VD therapy against NAFLD. • Vitamin D inhibited activation of NLRP3 inflammasome and pyroptosis in NAFLD rat. • Vitamin D might attenuate HFD-induced NAFLD by inhibiting pyroptosis in NAFLD rat. • Vitamin D restored HFD-induced gut microbiota dysbiosis in NAFLD rat. [ABSTRACT FROM AUTHOR]