Objective: To investigate the effect and molecular mechanism of dapagliflozin on epithelial-mesenchymal transformation and fibrosis of renal tubular epithelial cells in diabetic kidney disease. Methods: Human renal tubular epithelial cells HK-2 were cultured in vitro and divided into control group, high glucose group, low dose dapagliflozin + high glucose group and high dose dapagliflozin + high glucose group. The expression levels of Rffl were detected by Western blot and RT-PCR, respectively. The expression levels of epithelial cadherin(E-cadherin), α-smooth muscle actin(α-SMA), Fibronectin, transforming growth factor β1(TGF-β1) and signal transducerand activator of transcription 1(STAT1) were detected by Western blot. After Rffl was overexpressed in HK-2 cells, the expression levels of E-cadherin, α-SMA, Fibronectin, TGF-β1 and STAT1 were detected by Western blot. Results: The expression level of Rffl in the high glucose group was significantly lower than that in the control group, and the expression of Rffl was increased after adding dapagliflozin. Compared with the control group, the expression level of E-Cadherin in the high glucose group was decreased, while the expression level of Fibronectin and α-SMA was increased. After Rffl was overexpressed in cells, the expression level of E-Cadherin was increased, while the expression levels of Fibronectin and α-SMA were decreased. Compared with high glucose group, the expression levels of E-Cadherin in low-dose dapagliflozin + high glucose group and high-dose dapagliflozin + high glucose group were increased, but the expression levels of Fibronectin and α-SMA were decreased, in a dose-dependent manner. Compared with the control group, the expression levels of STAT1 and TGF-β1 were increased in the high glucose group, but significantly decreased after overexpression of Rffl or addition of dapagliflozin. Conclusion: Dapagliflozin inhibits STAT1/TGF-β1 signaling pathway by up-regulating Rffl expression, and improves epithelial-mesenchymal transformation and fibrosis of renal tubular epithelial cells in diabetic kidney disease.