An Artemisinin Derivative ART1 Induces Ferroptosis by Targeting the HSD17B4 Protein Essential for Lipid Metabolism and Directly Inducing Lipid Peroxidation

作     者：Jingjing Xie Guangya Zhu Ming Gao Jie Xi Ge Chen Xinxin Ma Yu Yan Zhiyuan Wang Ze-Jun Xu Hui-Jun Chen Hong-Dong Hao Yaoyang Zhang Zhu-Jun Yao Jidong Zhu 

作者机构：Interdisciplinary Research Center on Biology and ChemistryShanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 201203 University of the Chinese Academy of SciencesBeijing 100049 State Key Laboratory of Coordination ChemistryJiangsu Key Laboratory of Advanced Organic MaterialsSchool of Chemistry and Chemical EngineeringNanjing UniversityNanjingJiangsu 210023 School of Life SciencesWestlake UniversityHangzhou 310012 Department of Translational Research in PsychiatryMax Planck Institute of PsychiatryMunich 80804 State Key Laboratory of Bioorganic and Natural Products ChemistryShanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032 Center for Excellence in Molecular SynthesisShanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032 

出 版 物：《CCS Chemistry》 (中国化学会会刊（英文）)

年 卷 期：2022年第4卷第1期

页      面：304-317页

学科分类：081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 070303[理学-有机化学] 0703[理学-化学] 

基　　金：supported by the National Natural Science Foundation of China(no.21532002 to Z.-J.Y.and J.Z. no.21761142001 to Z.-J.Y.) 

主　　题：artemisinin derivative antitumor ferroptosis HSD17B4 selectivity mesenchymal 

摘      要：Artemisinin and its derivatives,commonly known as antimalarial drugs,have gradually come to be regarded as potential antitumor agents,although their cytotoxic efficacy and mechanisms of action remain to be ***,we report that an artemisinin analog,ART1,can potently induce ferroptosis in a subset of cancer cell ***–activity relationship(SAR)analysis reveals that both the endoperoxide moiety and the artemisinin skeleton are required for the antitumor activity of *** with ART1-based small-molecule tools,chemical proteomic analysis identified the HSD17B4 protein as a direct target of ***17B4 resides in peroxisomes and is an essential enzyme in the catabolism of very-long-chain fatty *** results demonstrate that ART1 initiates ferroptosis through selective oxidation of the fatty acids in peroxisomes by hijacking the HSD17B4 protein without disturbing its enzymatic function,providing a promising mechanism to develop therapeutics for cancer treatment.