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LETTERS TO THE EDITOR

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

Renhong Yan^1,8,† , Enjun Xie^2,3,† , Yaning Li^4,† , Jin Li^2,3,† , Yuanyuan Zhang¹ , Ximin Chi¹ , Xueping Hu⁵ , Lei Xu⁶ , Tingjun Hou⁵ , Brent R. Stockwell⁷ , Junxia Min^2,* , Qiang Zhou^1,* , Fudi Wang^2,3,*

¹Westlake 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
²he 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
³The First Affiliated Hospital, The Second Affiliated Hospital, Basic Medical Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, Hunan, China
⁴Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
⁵Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
⁶Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou, Jiangsu, China
⁷Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY, USA
⁸Present address: Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
^†These authors contributed equally: Renhong Yan, Enjun Xie, Yaning Li, Jin Li
* Correspondence: Junxia Min(junxiamin@zju.edu.cn)Qiang Zhou(zhouqiang@westlake.edu.cn)Fudi Wang(fwang@zju.edu.cn)

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).1,2,3,4 Recent studies have shown that xCT (SLC7A11) regulates ferroptosis in liver fibrosis, cardiomyopathy, and numerous other pathophysiological processes.5,6,7,8 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).

https://doi.org/10.1038/s41422-022-00642-w

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