Diabetic kidney disease (DKD) constitutes a major microvascular sequela of diabetes mellitus. Ferroptosis, a distinct cell death modality contingent upon ferrous ion dysregulation, is involved in the pathogenesis of DKD. Celastrol is an active compound isolated from Tripterygium wilfordii , which has anti-inflammatory and antioxidant properties and is related to the improvement of DKD, but its exact molecular basis has not been fully determined. This study aimed to determine whether celastrol attenuates renal tubular ferroptosis in early DKD through modulation of NADPH oxidase 2 (NOX2) expression. Renal tissue samples from patients with early DKD and controls were analyzed for ferroptosis-related pathological changes using Perls staining, immunohistochemistry, and transmission electron microscopy. In addition, we established an early DKD rat model in which the animals were treated with celastrol to investigate its molecular mechanisms of action. The results showed that renal tissue from patients with early DKD and model rats had increased iron deposition, reduced glutathione peroxidase 4 (GPX4) expression, lipid peroxide accumulation, and mitochondrial structural damage. Celastrol reversed these pathological changes while significantly reducing urinary protein levels. Additionally, NOX2 expression was significantly elevated in early DKD renal tissue but was effectively suppressed by celastrol. The NOX2 agonist PMA co-treatment partially abrogated the renoprotective effects of celastrol. Collectively, these findings demonstrate that celastrol ameliorates ferroptosis-mediated renal tubular injury in early DKD, and this protective mechanism is associated with the downregulation of NOX2 expression. This study furnishes preliminary evidence for investigating celastrol's mechanistic role against early DKD. • Ferroptosis is observed in both early diabetic kidney disease patients and rat models. • Aberrant upregulation of NOX2 in early diabetic kidney disease. • Celastrol ameliorates renal injury in a early diabetic kidney disease rat model. • Celastrol ameliorates early diabetic renal tubular injury possibly via ferroptosis suppression. • The use of the NOX2 agonist PMA partially reversed the renal protective effects of celastrol.
Ma et al. (2026) studied this question.