2. Academic Validation
  3. Crizotinib and its enantiomer suppress ferroptosis by decreasing PE-O-PUFA content

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

  • Cell Death Discov. 2024 Aug 12;10(1):360. doi: 10.1038/s41420-024-02127-8.
Si-Yu Cen 1,  Fang Lin 2 3,  Xuan Li 2 3,  Yanglin Hu 4,  Jin-Pin Liu 1,  Zian Xue 5,  Yun Gao 1,  Yi-Ping Sun 1,  Sanyong Zhu 3,  Yongjun Dang 3,  Yahui Zhao 2 3,  Hai-Xin Yuan 6 7 8
Affiliations

Affiliations

  • 1 The Fifth People's Hospital of Shanghai, Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
  • 2 College of Pharmacy & Department of Cancer Center, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
  • 3 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.
  • 4 Department of Nephrology,, Wuhan No.1 hospital, Wuhan, 430022, China.
  • 5 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 200120, China.
  • 6 The Fifth People's Hospital of Shanghai, Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. yuanhaixin@fudan.edu.cn.
  • 7 College of Pharmacy & Department of Cancer Center, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China. yuanhaixin@fudan.edu.cn.
  • 8 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China. yuanhaixin@fudan.edu.cn.
PMID: 39134539 DOI: 10.1038/s41420-024-02127-8
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 (R)-crizotinib and (S)-crizotinib in Ferroptosis regulation. As a clinically approved drug, (R)-crizotinib has well-established pharmacokinetics and safety, which makes it a promising candidate for repurposing. Given the current lack of FDA-approved Ferroptosis inhibitors, our findings suggest therapeutically repurposing (R)-crizotinib as well as its enantiomer (S)-crizotinib for treating ferroptosis-related diseases.

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