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

• Published in: International immunopharmacology 2022-11, Vol.112, p.109162-109162, Article 109162
• Main Authors: Qiu, Weihuang, An, Sheng, Wang, Tingjie, Li, Jiaxin, Yu, Binmei, Zeng, Zhenhua, Chen, Zhongqing, Lin, Bo, Lin, Xianzhong, Gao, Youguang
• Format: Article
• Language: English
• Subjects: Acute kidney injury; Ferroptosis; HO-1; Melatonin; Nrf2; Sepsis
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2022.109162

•Ferroptosis levels increased in sepsis-induced acute kidney injury mouse model.•Ferostatin-1 inhibits Ferroptosis and alleviates sepsis-induced acute kidney injury.•Melatonin improves sepsis-induced acute kidney injury by inhibiting Ferroptosis.•Melatonin inhibits Ferroptosis via up regulating Nrf2/HO-1. 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 ferroptosis inhibitor, but it is unclear whether Melatonin can regulate ferroptosis in SAKI and whether its downstream mechanism correlates with the Nrf2/HO-1 pathway. 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. 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. Ferroptosis aggravates SAKI. Melatonin treatment suppresses ferroptosis and alleviates kidney injury in the context of experimental sepsis by upregulating Nrf2/HO-1 pathway.