Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and podocyte injury is one of the major contributors to DKD. As a crucial transcriptional factor that regulates cellular response to oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) is an attractive therapeutic target for DKD. In this study, we evaluated the therapeutic potential of DDO-1039, a novel small-molecule Nrf2 activator developed with protein-protein interaction strategy, on podocyte injury in DKD. DDO-1039 treatment significantly increased Nrf2 protein level and Nrf2 nuclear translocation, thereby upregulating Nrf2 target genes [heme oxygenase 1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase modifier, and tyrosine-protein kinase receptor] both and . DDO-1039 attenuated glomerular sclerosis and podocyte injury in the high-fat diet/streptozotocin-induced (HFD/STZ) diabetic mice and db/db diabetic mice. It also significantly improved hyperglycemia in both diabetic mice and mitigated proteinuria in HFD/STZ mice. Meanwhile, DDO-1039 attenuated oxidative stress and inflammation as well as apoptosis and in podocytes stimulated with palmitic acid and high glucose. Interestingly, we identified podocyte protective factor Tyro3 as a novel Nrf2-regulated gene. In addition, podocyte ferroptosis is reduced activation of glutathione peroxidase 4 by the novel Nrf2 activator. DDO-1039 activates the Nrf2-based cytoprotective system to mitigate podocyte injury in the context of diabetes, suggesting the potential of DDO-1039 in the treatment of DKD. 42, 787-806.