Hyperoside attenuates diabetic nephropathy by activating the Nrf2/SLC7A11/GPX4 axis to restrain ferroptosis

BACKGROUND Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Despite their ability to delay the progression of DN, current therapies do not halt renal injury. Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, contributes to DN pathogenesis. AIM To test the hypothesis that hyperoside—a natural flavonoid—protects against DN by activating the Nrf2/SLC7A11/GPX4 antioxidant signaling pathway, thereby reducing ferroptosis and oxidative stress-related renal injury. METHODS High-glucose-treated HK-2 cells and streptozotocin-induced DN rats were used to evaluate the effects of hyperoside. Cell viability, apoptosis, oxidative stress, and ferroptosis markers were measured using Cell Counting Kit-8, terminal deoxynucleotidyl transferase dUTP nick-end labeling, flow cytometry, enzyme-linked immunosorbent assay, quantitative reverse transcription polymerase chain reaction, and Western blotting. Mechanistic validation was performed using erastin, ferrostatin-1, and Nrf2 small interfering RNAs. RESULTS Hyperoside significantly improved HK-2 cell viability under high-glucose conditions and reduced apoptosis, with 50 μmol/L showing the most consistent protection. It decreased lactate dehydrogenase, malondialdehyde, Fe2+, and lipid reactive oxygen species levels and restored glutathione as well as Nrf2, SLC7A11, and GPX4 expression, effects comparable to the ferroptosis inhibitor ferrostatin-1 (all P < 0.05). In streptozotocin-induced DN rats, hyperoside (50 mg/kg) lowered serum creatinine, blood urea nitrogen, and urinary albumin excretion, ameliorated glomerular and tubular lesions, and upregulated renal Nrf2/SLC7A11/GPX4 expression (all P < 0.05). CONCLUSION Hyperoside alleviates diabetic renal injury by activating the Nrf2/SLC7A11/GPX4 pathway and suppressing ferroptosis-driven oxidative damage. These findings provide mechanistic and experimental evidence supporting hyperoside as a potential therapeutic candidate for DN.