〔Abstract〕 Objective To explore the pathogenesis of diabetic peripheral neuropathy based on the mitochondrial pathway regulated by SREBP-2/Lipin1. Methods 60 male SD rats, 20 rats as control group, 40 rats were given high-sugar high-fat diet combined with intraperitoneal injection of streptozotocin(STZ) induced diabetic mellitus(DM) rat model, feeding for 6 weeks, DPN model was established successfully when the rat tail sciatic nerve conduction veloeity(SNCV)<30 m/s. Selected ten rats in the normal control group and 10 rats in the DPN model group, the content of reactive oxygen species(ROS), SREBP-2 and Lipin1 protein expression in the sciatic nerve were detected. In addition, 30 diabetic peripheral neuropathy(DPN) rats were randomly divided into empty vector(NC) group, SREBP-2-siRNA(si-SREBP-2) group, Lipin1 over expression(LV-lipin1) group.The si-SREBP-2 group were injected with SREBP-2-siRNA through the tail vein, the LV-lipin1 and LV-control groups were respectively injected with Lipin1 lentivirus vector and empty lentivirus vector through the tail vein. The SREBP-2 and Lipin1 protein expression in the sciatic nerve were detected. After 8 weeks, the fasting plasma glucose and SNCV were observed. The mitochondrial membrane potential, ROS, Bcl-2, Bax, Cyto C in sciatic nerve were detected. Results Compared with the control group, ROS content and SREBP-2 protein expression were significantly increased in the DPN group, while the Lipin1 protein expression was significantly decreased in the DPN group. After regulated the expression of SREBP-2 and Lipin1, compared with the NC group, the SREBP-2 protein expression was significantly decreased while the Lipin1 protein expression was significantly increased in the DPN group. Fasting blood glucose significantly decreased, the SNCV significantly increased. Mitochondrial membrane potential significantly increased; The content of ROS significantly reduced. The protein expressions of Cyto C and Bcl-2 were significantly increased, while the protein expression of Bax was significantly decreased. Conclusion The SREBP-2 and Lipin1 expression are abnormal in the sciatic nerve of DPN rats, regulating SREBP-2 and Lipin1 can improve the sciatic neuropathy of DPN rats, indicating that the pathogenesis of DPN is related to the mitochondrial pathway regulated by srebp-2 and Lipin1.