铁死亡是近期发现的有别于凋亡的一种细胞死亡新方式，诱导铁死亡可产生显著的抗肿瘤作用，深入研究其分子调控过程可为抗肿瘤药物研发提供全新策略。我们前期研究发现DJ-1蛋白对铁死亡具有重要的调控作用，是一个全新的铁死亡负性调控蛋白，这一作用与其同源二聚化结构以及蛋白去糖化酶活密切相关。在此基础上，本项目将系统研究DJ-1蛋白负性调控铁死亡的作用，阐明其同源二聚化结构对蛋白去糖化酶活和铁死亡的影响，并深入探讨前期发现的谷胱甘肽合成代谢通路在这一过程中的关键作用，明确该通路中的关键蛋白CBS是否作为DJ-1的酶活底物参与铁死亡的调控，同时采用已获得的DJ-1同源二聚化抑制剂探索DJ-1作为治疗靶点诱导肿瘤细胞铁死亡的可能性。本项目将有望发现铁死亡调控的全新信号通路和DJ-1蛋白的新生物学功能，发展基于铁死亡调控的抗肿瘤药物研发新策略，具有重要的理论意义和临床价值。

Ferroptosis is a new type of cell death that is different from apoptosis. Induction of ferroptosis can produce significant antitumor effects, therefore, the study on its mechanism could provide a novel strategy for the development of anticancer drug. Our previous studies have found that DJ-1 protein plays an important role in the regulation of ferroptosis and might be a novel negative regulator of ferroptosis. Further studies found that this effect is highly modulated by its homologous dimerization structure and protein deglycase activity. Therefore, we will further evaluate the function of DJ-1 in the regulating of ferroptosis, and test the effect of its homologous dimerization structure in its protein deglycase activity and ferroptosis. Moreover, we will determine the role of glutathione synthesis pathway and confirm whether CBS protein is the substrate for DJ-1. Finally, we will use the obtained DJ-1 homologous dimerization inhibitor to explore whether DJ-1 could be drug target based on ferroptosis induction. Our study will not only provide a new insight for the mechanism of ferroptosis and novel function of DJ-1 protein, but also advance the development of a new therapeutic strategy for ferroptosis-based anticancer drugs.