摘要Sodium-glucose co-transporter 2(SGLT2)inhibitor(SGLT2i)is a novel class of anti-diabetic drug,which has displayed a promising benefit for non-alcoholic fatty liver disease(NAFLD).In this study,we investigated the protective effects of SGLT2i against NAFLD and the underlying mechanisms.The db/db mice and western diet-induced NAFLD mice were treated with dapagliflozin(1 mg·kg-1·d-1,i.g.)or canagliflozin(10 mg·kg-1·d-1,i.g.)for 8 weeks.We showed that the SGLT2i significantly improved NAFLD-associated metabolic indexes,and attenuated hepatic steatosis and fibrosis.Notably,SGLT2i reduced the levels of pro-inflammatory cytokines and chemokines,downregulated M1 macrophage marker expression and upregulated M2 macrophage marker expression in liver tissues.In cultured mouse bone marrow-derived macrophages and human peripheral blood mononuclear cell-derived macrophages,the SGLT2i(10,20 and 40μmol/L)significantly promoted macrophage polarization from M1 to M2 phenotype.RNA sequencing,Seahorse analysis and liquid chromatography-tandem mass spectrometry analysis revealed that the SGLT2i suppressed glycolysis and triggered metabolic reprogramming in macrophages.By using genetic manipulation and pharmacological inhibition,we identified that the SGLT2i targeted PFKFB3,a key enzyme of glycolysis,to modulate the macrophage polarization of M1 to M2 phenotype.Using a co-culture of macrophages with hepatocytes,we demonstrated that the SGLT2i inhibited lipogenesis in hepatocytes via crosstalk with macrophages.In conclusion,this study highlights a potential therapeutic application for repurposing SGLT2i and identifying a potential target PFKFB3 for NAFLD treatment.