Tripterygium glycoside (TG) is a traditional Chinese medicine extract with immunosuppressive, anti?inflammatory and anti?renal fibrosis effects. Epithelial?mesenchymal transition (EMT) and cell apoptosis are considered to be the major cause of podocyte injury in diabetic kidney disease?(DKD). However, it remains unknown as to whether TG is able to alleviate podocyte injury to prevent DKD progression. Therefore, the present study aimed to clarify the podocyte protective effects of TG on DKD. TG, Twist1 small interfering RNA (siRNA) and Twist1 overexpression vector were added to DKD mouse serum?induced podocytes . Autophagic and EMT activities were evaluated by immunofluorescence staining and western blot analysis. Apoptotic activity was evaluated by Annexin?V?FITC/PI flow cytometric analysis. The results revealed that after treatment with DKD mouse serum, autophagy was decreased, whereas EMT and apoptotic rate were increased, in podocytes. In addition, Twist1 expression was increased in DKD?induced podocytes. Furthermore, following Twist1?small interfering RNA transfection, the DKD?induced podocyte EMT and apoptotic rate were markedly reduced, indicating that Twist1 may be a promising therapeutic target for DKD. The present results also revealed that overexpression of Twist1 increased podocyte apoptosis, although this was decreased after TG treatment, indicating that TG may exhibit a protective effect on podocytes by inhibiting the Twist1 signaling pathway. After the addition of 3?benzyl?5?((2?nitrophenoxy) methyl)?dihydrofuran?2(3H)?one, an activator of mTORC1, the effects of TG on podocyte EMT, apoptosis and the autophagy were reversed. These findings indicated that TG may alleviate EMT and apoptosis by upregulating autophagy through the mTOR/Twist1 signaling pathway in DKD.