Dear Editor, Ferroptosis is an iron-dependent,non-apoptotic form of regulated cell death characterized by an accumulation of lipid-derived reactive oxygen species(ROS).The small-molecule compound erastin induces ferroptosis via inhibiting the cystine-glutamate antiporter system xc-,which consists of two subunits,namely the light chain xCT and the heavy chain 4F2hc(encoded by the SLC7A11 and SLC3A2 genes,respectively).1-4 Recent studies have shown that xCT(SLC7A11)regulates ferroptosis in liver fibrosis,cardiomyopathy,and numerous other pathophysiological processes.5-8 The complex formed by xCT and 4F2hc has also been suggested as a possible therapeutic target for cancer,as it is overexpressed in a wide variety of cancer types;moreover,inhibiting xCT impairs cystine uptake,causing an accumulation of ROS and suppressing tumor growth.9,10 However,the underlying molecular mechanisms remain unknown.Here,we overexpressed and then co-purified human xCT and 4F2hc,finding that they form a stable complex(Fig.1a).To test whether this purified complex is functional,we then reconstituted the complex into liposomes and performed a counter-flow assay.We found that the wild-type(WT)xCT-4F2hc complex mediates the exchange of cystine and glutamate—measured as the uptake of 14C-labeled cystine—and this activity was significantly reduced by the system xc-inhibitors,erastin and sulfasalazine(Supplementary information,Fig.S1).

Renhong Yan;Enjun Xie;Yaning Li;Jin Li;Yuanyuan Zhang;Ximin Chi;Xueping Hu;Lei Xu;Tingjun Hou;Brent R.Stockwell;Junxia Mini;Qiang Zhou;Fudi Wang

Westlake Laboratory of Life Sciences and Biomedicine,Key Laboratory of Structural Biology of Zhejiang Province,Institute of Biology,Westlake Institute for Advanced Study,School of Life Sciences,Westlake University,Hangzhou,Zhejiang,China;Department of Biochemistry,School of Medicine,Southern University of Science and Technology,Shenzhen,Guangdong,China;The First Affiliated Hospital,The Fourth Affiliated Hospital,School of Public Health,Institute of Translational Medicine,Cancer Center,State Key Laboratory of Experimental Hematology,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China;The First Affiliated Hospital,The Second Affiliated Hospital,Basic Medical Sciences,School of Public Health,Hengyang Medical School,University of South China,Hengyang,Hunan,China;Beijing Advanced Innovation Center for Structural Biology,Tsinghua-Peking Joint Center for Life Sciences,School of Life Sciences,Tsinghua University,Beijing,China;Hangzhou Institute of Innovative Medicine,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,Zhejiang,China;Institute of Bioinformatics and Medical Engineering,Jiangsu University of Technology,Changzhou,Jiangsu,China;Department of Biological Sciences and Department of Chemistry,Columbia University,New York,NY,USA

细胞研究（英文版）

[1]Renhong Yan;Enjun Xie;Yaning Li;Jin Li;Yuanyuan Zhang;Ximin Chi;Xueping Hu;Lei Xu;Tingjun Hou;Brent R.Stockwell;Junxia Mini;Qiang Zhou;Fudi Wang-.The structure of erastin-bound xCT-4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis)[J].细胞研究（英文版）,2022(07):687-690

4F2hc, Ferroptosis

structure,erastin,bound,xCT,complex,reveals,molecular,mechanisms,underlying,induced,ferroptosis,Dear,Editor,iron,dependent,apoptotic,regulated,cell,death,characterized,by,accumulation,lipid,derived,reactive,oxygen,species,ROS,small,molecule,compound,induces,via,inhibiting,cystine,glutamate,antiporter,system,which,consists,two,subunits,namely,light,chain,heavy,encoded,SLC7A11,SLC3A2,genes,respectively,Recent,studies,have,shown,that,regulates,liver,fibrosis,cardiomyopathy,numerous,other,pathophysiological,processes,has,also,been,suggested,possible,therapeutic,target,cancer,overexpressed,wide,variety,types,moreover,impairs,uptake,causing,suppressing,tumor,growth,However,remain,unknown,Here,then,purified,human,finding,they,stable,Fig,1a,To,test,whether,this,functional,reconstituted,into,liposomes,performed,counter,flow,assay,We,found,wild,WT,mediates,exchange,measured,14C,labeled,activity,was,significantly,reduced,inhibitors,sulfasalazine,Supplementary,information,S1

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