Leonurine alleviates ferroptosis in cisplatin-induced acute kidney injury by activating the Nrf2 signalling pathway

Background and purpose Evidence indicates that ferroptosis plays a key role in acute kidney injury induced by cisplatin. The Nrf2/NRF2 pathway regulates oxidative stress, lipid peroxidation and positively regulates cisplatin-induced acute kidney injury, but its effect along with the alkaloid leonurine, found in motherwort, on ferroptosis after such acute kidney injury remains unclear. Experimental Approach The anti-ferroptotic effects of Nrf2 and leonurine were assessed in a mouse model of cisplatin-induced acute kidney injury. In vitro, the effects of leonurine on erastin- and RSL3-induced HK-2 human PTEC ferroptosis were examined. Key Results Nrf2 deletion induced ferroptosis-related protein expression and iron accumulation in vivo, aggravating cisplatin-induced acute kidney injury. Leonurine activated Nrf2 and prevented iron accumulation, lipid peroxidation and ferroptosis in vitro, being abolished in siNrf2-treated cells. Moreover, leonurine potently inhibited cisplatin-induced renal damage, as assessed by of serum creatinine, blood urea nitrogen, kidney injury molecule-1 and NGAL. Importantly, leonurine activated the Nrf2 antioxidative pathway and preventing changes in ferroptosis-related morphological and biochemical indicators, malondialdehyde level, SOD and GSH depletion, and GPX4 and xCT down-regulation, in cisplatin-induced acute kidney injury. Nrf2 KO mice were more susceptible to ferroptosis after cisplatin-induced acute kidney injury than control mice. The protective effects of leonurine on acute kidney injury and ferroptosis were largely abolished in Nrf2 KO mice. Conclusion and Implications These data suggest that renal protective effects of Nrf2 activation on cisplatin-induced acute kidney injury are achieved, at least partially, by inhibiting lipid peroxide-mediated ferroptosis, highlighting the potential of leonurine in acute kidney injury treatment.