The structure of erastin-bound xCT–4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis

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).