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.