Oleanolic Acid Alleviates Diabetic Nephropathy by Inhibiting Ferroptosis Involving the Activation of the NRF2/HO-1 Pathway

Abstract Oleanolic acid (OA), a pentacyclic triterpenoid found in agricultural products such as grapes and olives, exhibits potential in alleviating diabetic nephropathy (DN). We validated its renoprotective effects using high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mice and high glucose-stimulated HK-2 cells. Network pharmacology predicted ferroptosis and the NRF2/HO-1 axis as key targets, which was supported by molecular docking and dynamics simulations indicating stable binding. Mechanistically, OA treatment upregulated the NRF2/HO-1 pathway, which was associated with the inhibition of ferroptosis─evidenced by suppressed lipid peroxidation and iron overload, improved mitochondrial function, and the regulation of key proteins (e.g., upregulating GPX4 and the iron-storage protein FTH1, while downregulating ACSL4). Its antiferroptotic effects were mimicked by the specific inhibitor Ferrostatin-1 (Fer-1) and abolished by the inducer Erastin (Era). Collectively, this study suggests that OA protects against DN potentially through modulating the NRF2/HO-1 axis to mitigate ferroptosis, supporting its potential as a promising bioactive dietary compound for the management of DN.