Abstract: Objective: To explore the effect of peroxidase 5 (PEX5) on podocyte damage induced by high glucose (HG) in vitro and its related mechanisms. Methods: Differentially expressed genes (DEGs) in diabetic ob/ob mouse vs.non-diabetic ob/m mouse kidneys were obtained from GSE106841 dataset.The protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes (STRING),and gene ontology (GO) and KEGG enrichment analysis were performed on the identified DEGs.Twelve mice were randomly divided into normal group and STZ-induced diabetic nephropathy (DN) group,with 6 mice in each group.Immunohistochemistry and Western blotting were used to detect the expression of PEX5 and peroxisome proliferator-activated receptor α (PPARα) in mouse kidney tissues and cells.MPC-5 renal podocytes treated with HG were used to simulate DN in vitro.Cell apoptosis were detected by flow cytometry.MPC-5 cells with up-regulated and down-regulated PEX5 were constructed to investigate the effects of PEX5 on the apoptosis of MPC-5 podocytes induced by HG. Results: PEX5 was an important hub gene of the PPI network,and it was mainly involved in PPAR signaling pathway.It was confirmed by in vitro and in vivo studies that PEX5 and PPARα expression was significantly reduced in kidney tissues of DN group mice and cells of HG group.In vitro experiments showed that PEX5 inhibition not only reduced PPARα expression in podocytes,but also increased apoptosis.PEX5 overexpression reversed the effects of HG on inhibiting PEX5 and PPARα protein expression,and reduced apoptosis. Conclusions: Up-regulation of PEX5 reduces HG-induced podocyte apoptosis by activating the PPARα signaling pathway.