Crizotinib and its enantiomer suppress ferroptosis by decreasing PE-O-PUFA content

作者：Si-Yu Cen, Fang Lin, Xuan Li, Yanglin Hu, Jin-Pin Liu, Zian Xue, Yun Gao, Yiping Sun, Sanyong Zhu, Yongjun Dang, Yahui Zhao, Hai‐Xin Yuan · 发表于：Cell Death Discovery · 年份：2024 · DOI：10.1038/s41420-024-02127-8 · 被引用次数：5 · 研究领域：Ferroptosis and cancer prognosis、Cancer, Lipids, and Metabolism、Lung Cancer Treatments and Mutations

Abstract Ferroptosis is a specific form of cell death characterized by excessive accumulation of cellular lipid peroxides. Ferroptosis is closely associated with various diseases, inhibition of which may help alleviate multi-organ injury caused by ischemia-reperfusion and enhance the anti-tumor effect by promoting the immunity of T cells. However, clinical approved drugs targeting ferroptosis process remain rare. In this study, we unexpectedly found that (R)-crizotinib, the first-generation ALK inhibitor, has potent inhibitory activity against ferroptosis across various cell lines. Moreover, its chiral molecule (S)-crizotinib, which was considered to share no common targets with (R)-crizotinib, also suppresses ferroptosis with an efficacy similar to that of (R)-crizotinib. We further demonstrated that both crizotinib enantiomers inhibit ferroptosis independently of their known targets, but through a common mechanism involving the targeting of AGPAT3-mediated synthesis of ether-linked polyunsaturated fatty acids (PE-O-PUFA), which are known to promote lipid-ROS generation and ferroptosis. In line with their activity in cell lines, (R)-crizotinib and (S)-crizotinib effectively mitigate renal ischemia-reperfusion injury in mice. Furthermore, the two compounds also inhibit lipid-ROS accumulation in CD8 + T cells in draining lymph nodes of B16-F10 subcutaneous xenograft mice, thereby promoting anti-tumor effects. Collectively, our study firstly reports a common activity shared by ...