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 settled.Her...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 settled.Herein,we report that an artemisinin analog,ART1,can potently induce ferroptosis in a subset of cancer cell lines.Structure–activity relationship(SAR)analysis reveals that both the endoperoxide moiety and the artemisinin skeleton are required for the antitumor activity of ART1.Aided with ART1-based small-molecule tools,chemical proteomic analysis identified the HSD17B4 protein as a direct target of ART1.HSD17B4 resides in peroxisomes and is an essential enzyme in the catabolism of very-long-chain fatty acids.Our 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.展开更多
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.).
文摘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 settled.Herein,we report that an artemisinin analog,ART1,can potently induce ferroptosis in a subset of cancer cell lines.Structure–activity relationship(SAR)analysis reveals that both the endoperoxide moiety and the artemisinin skeleton are required for the antitumor activity of ART1.Aided with ART1-based small-molecule tools,chemical proteomic analysis identified the HSD17B4 protein as a direct target of ART1.HSD17B4 resides in peroxisomes and is an essential enzyme in the catabolism of very-long-chain fatty acids.Our 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.
