Celastrol mitigates diabetic kidney disease by inhibiting ferroptosis via the SIRT1/NRF2/GPX4 pathway

Diabetic kidney disease (DKD) is a leading cause of end-stage renal failure. Ferroptosis, an iron-dependent form of lipid peroxidation, contributes to DKD pathogenesis in diabetic mice. Celastrol, a bioactive compound derived from Tripterygium wilfordii, mitigates DKD-related renal injury, however, its effects and mechanisms concerning diabetes-associated ferroptosis remain undefined. Using a db/db mice model, we compared celastrol, losartan, and ferrostatin-1 (Fer-1) in mitigating renal damage via the ferroptosis pathway. We assessed biochemical indices, renal histopathology, ferroptosis markers (GSH, MDA, SOD, and iron levels), and signalling pathways. In vitro, HK-2 cells models were employed to analyse ferroptosis in renal tubular cells and protein expression. Celastrol treatment significantly improved renal function (reduced serum creatinine and 24 h proteinuria), attenuated dyslipidemia, and ameliorated ferroptosis indicators by increasing GSH and SOD while lowering MDA and iron accumulation. Further experiments suggested that celastrol upregulated SIRT1/NRF2/GPX4 signalling pathway proteins. Moreover, EX527-mediated SIRT1 inhibition abolished celastrol’s anti-ferroptotic effects in vitro. Both losartan and Fer-1 treatment improved renal function, reduced oxidative stress, and mitigated lipid peroxidation in DKD mice. These findings demonstrate that celastrol alleviates DKD-associated renal injury by inhibiting ferroptosis via activation of the SIRT1/NRF2/GPX4 signalling pathway.