Ferroptosis is a unique type of cell death that is hallmarked with the imbalanced redox homeostasis as triggered by iron-dependent lipid peroxidation. Cysteines often play critical roles in proteins to help maintain a healthy cellular environment by dynamically switching between their reduced and oxidized forms, however, how the global redox landscape of cysteinome is perturbed upon ferroptosis remains unknown to date. By using a quantitative chemical proteomic strategy, we systematically profiled the dynamic changes of cysteinome in ferroptotic cells and identified a list of candidate sites whose redox states are precisely regulated under ferroptosis-inducing and rescuing conditions. In particular, C106 of the protein/nucleic acid deglycase DJ-1 acts as an intriguing sensor switch for the ferroptotic condition, whose oxidation results in the disruption of its interaction with the 20S proteasome and leads to a marked activation in the proteasome system. Our chemoproteomic profiling and associated functional studies reveal a novel functional link between ferroptosis and the proteasome-mediated protein degradation. It also suggests proteasome as a promising target for developing treatment strategies for ferroptosis-related diseases.

Ferroptosis 是一种独特的细胞死亡类型，其特点是铁依赖性脂质过氧化引发的氧化还原稳态失衡。半胱氨酸通常在蛋白质中发挥关键作用，通过在还原和氧化形式之间动态切换来帮助维持健康的细胞环境，然而，迄今为止，半胱氨酸组的全球氧化还原景观如何因铁死亡而受到干扰仍然未知。通过使用定量化学蛋白质组学策略，我们系统地描述了铁死亡细胞中半胱氨酸组的动态变化，并确定了一系列候选位点，这些位点的氧化还原状态在铁死亡诱导和拯救条件下受到精确调节。特别是，蛋白质/核酸去糖酶 DJ-1 的 C106 作为铁死亡条件的有趣传感器开关，其氧化导致其与 20S 蛋白酶体的相互作用中断，并导致蛋白酶体系统显着激活。我们的化学蛋白质组学分析和相关的功能研究揭示了铁死亡和蛋白酶体介导的蛋白质降解之间的新功能联系。它还表明蛋白酶体是开发铁死亡相关疾病治疗策略的有前途的目标。