电离辐射通过破坏体内氧化还原系统平衡引起细胞损伤。胱氨酸/谷氨酸反向转运体 (System Xc-)由CD98和xCT亚单位构成，CD98负责招募xCT到质膜,xCT参与谷胱甘肽(GSH) 合成和胱氨酸的跨膜穿梭，发挥抗氧化应激作用。我们研究发现，xCT参与辐射诱导的铁依赖性ROS产生和铁死亡的调控。本项目拟开展xCT调控辐射损伤和铁死亡机制研究：首先证实xCT参与辐射诱导的铁死亡过程，继而分别从转录调控（辐射敏感转录因子EGR1、Nrf2和ATF4对 xCT调控）、翻译调控（xCT与CD71、HSP90AB互做调控）、翻译后调控（MEK、mTORC2对xCT磷酸化调控）阐明xCT作用机制，最后从整体水平（动物实验、人体标本）验证xCT在辐射损伤中的作用。本研究将丰富辐射损伤及细胞死亡调控机制，通过抑制铁死亡防治辐射损伤，寻找候选靶点和药物，具有重要的理论价值和潜在的应用价值。

It is well known that ionizing radiation could increase the ROS production and change the balance between the oxidative and antioxidative systems, consequently induce radiation injury. The cystine/glutamate antiporter (system Xc −) transports cystine into cell in exchange for glutamate，consisting of CD98 and xCT, and xCT is in charge of the input of cystine and the output of glutamate, and the synthesis of glutathione. Our previous data found that xCT participated in the radiation-induced iron-dependent ROS production and ferroptosis. In this study the following aspects will be included: (1) to verify the roles of xCT in the radiation-induced ferroptosis; (2) trnascriptionally regulative mechanism: to confirm the EGR1,Nrf2 and ATF4 regulation of xCT; (3) xCT expression and the interaction between proteins: to confirm the roles of CD71-xCT and HSP90AB-xCT pathways; (4) post-trnascriptionally regulative mechanism: to confirm the roles of MEK/mTORC2 in the phosphorylation of xCT; (5) In vivo trials: to confirm the roles of xCT in the radiation killing on both normal tissues and exografts, and assess the injury and treatment efficacy. The above-mentioned research will fulfill the underlying mechanisms of radiation injury and figure out the potential targets and drugs via the suppression of ferroptosis mechanism, which show a promising theoretical value and application prospect.