Dendrobine Attenuates Cisplatin-Induced Acute Kidney Injury with KEAP1–NRF2 Activation and Reduced Ferroptosis-Associated Stress

Acute kidney injury (AKI) lacks effective pharmacological therapies, and ferroptosis-associated lipid peroxidation contributes to renal tubular injury. Here, we investigated the protective effects of dendrobine against AKI and its mechanisms. Dendrobine was evaluated in murine cisplatin-induced AKI and renal ischemia–reperfusion (I/R) models and in cisplatin- and erastin-challenged HK-2 cells using functional, histological, biochemical, and molecular analyses. Dendrobine improved renal function, alleviated tubular injury, reduced oxidative stress and lipid peroxidation, and preserved the GPX4/SLC7A11 antioxidant defense system in cisplatin-induced AKI and renal tubular cells. Dendrobine also attenuated erastin-associated lipid peroxidation and glutathione depletion, supporting an effect on ferroptosis-associated redox stress. Consistent renoprotective effects were observed in the renal I/R model. Mechanistically, target-engagement and protein-interaction analyses supported cellular engagement of KEAP1 by dendrobine and showed reduced KEAP1–NRF2 association and NRF2 ubiquitination, accompanied by enhanced NRF2 stabilization and nuclear accumulation. NRF2 inhibition attenuated the protective effects of dendrobine. Moreover, the KEAP1 R415A substitution attenuated dendrobine-associated KEAP1 engagement, NRF2 activation, and cytoprotection, supporting a functional contribution of Arg415 to these responses. Collectively, these findings support KEAP1–NRF2-regulated antioxidant defense as an important component of dendrobine-mediated protection against renal tubular injury and ferroptosis-associated stress in AKI.