Melatonin suppresses ferroptosis via activation of the Nrf2/HO-1 signaling pathway in the mouse model of sepsis-induced acute kidney injury

Background: Ferroptosis is a regulated form of cell death. At present, the role of ferroptosis in sepsis-induced acute kidney injury (SAKI) has not been studied. Melatonin (MEL) has been reported to be an effective ferrop-tosis inhibitor, but it is unclear whether Melatonin can regulate ferroptosis in SAKI and whether its downstream mechanism correlates with the Nrf2/HO-1 pathway.Methods: The cecal ligation and puncture (CLP) method and LPS injection were used to induce SAKI in mouse model. Ferroptosis markers, including malondialdehyde (MDA) and glutathione peroxidase 4 (GPX4), were assessed. The ferroptosis inhibitor ferrostatin-1 (Fer-1) was used to explore the role of ferroptosis in SAKI. The GPX4 inhibitor RSL3, the HO-1 inhibitor zinc protoporphyrin(ZnPP), and the Nrf2 inhibitor ML385 were used to explore the specific mechanism of MEL in alleviation of SAKI.Results: The ferroptosis level was increased in the renal tissue of CLP-and LPS-induced septic mice. Both Fer-1 and MEL administration could suppress ferroptosis and attenuate kidney injury upon sepsis challenge. RSL3 partially blocked MEL's beneficial renal-protective effects. MEL up-regulated Nrf2 and HO-1 in CLP mice, and both ZnPP and ML385 blocked the MEL-mediated effects of ferroptosis inhibition and renal protection.Conclusions: Ferroptosis aggravates SAKI. Melatonin treatment suppresses ferroptosis and alleviates kidney injury in the context of experimental sepsis by upregulating Nrf2/HO-1 pathway.