MCL attenuates atherosclerosis by suppressing macrophage ferroptosis via targeting KEAP1/NRF2 interaction

作者：Xing Luo, Yuehong Wang, Xinxin Zhu, Yuwu Chen, Biyi Xu, Xiaoxuan Bai, Xiuzhu Weng, Jinmei Xu, Yangyang Tao, Dan Yang, Jie Du, Ying Lv, Shan Zhang, Sining Hu, Ji Li, H.Y Jia · 发表于：Redox Biology · 年份：2023 · DOI：10.1016/j.redox.2023.102987 · 被引用次数：120 · 研究领域：Ferroptosis and cancer prognosis、Circular RNAs in diseases、MicroRNA in disease regulation

Micheliolide (MCL), also known as ACT001, which is the active metabolite of parthenolide, has demonstrated promising clinical application potential. However, the effects and underlying mechanisms of MCL on atherosclerosis are still unclear. ApoE−/− mice were fed with high fat diet, with or without MCL oral administration, then the plaque area, lipid deposition and collagen content were determined. In vitro, MCL was used to pretreat macrophages combined by ox-LDL, the levels of ferroptosis related proteins, NRF2 activation, mitochondrial function and oxidative stress were detected. MCL administration significantly attenuated atherosclerotic plaque progress, which characteristics with decreased plaque area, less lipid deposition and increased collagen. Compared with HD group, the level of GPX4 and xCT in atherosclerotic root macrophages were increased in MCL group obviously. In vitro experiment demonstrated that MCL increased GPX4 and xCT level, improved mitochondrial function, attenuated oxidative stress and inhibited lipid peroxidation to suppress macrophage ferroptosis induced with ox-LDL. Moreover, MCL inhibited KEAP1/NRF2 complex formation and enhanced NRF2 nucleus translocation, while the protective effect of MCL on macrophage ferroptosis was abolished by NRF2 inhibition. Additionally, molecular docking suggests that MCL may bind to the Arg483 site of KEAP1, which also contributes to KEAP1/NRF2 binding. Furthermore, Transfection Arg483 (KEAP1-R483S) mutant plasmid can abr...