SLC7A11介导的胱氨酸摄取能够抑制铁死亡，但在葡萄糖饥饿状态下促进细胞死亡；后者细胞死亡的性质仍然未知。本研究表明，在葡萄糖饥饿状态下，SLC7A11高表达细胞中胞内二硫键的异常积累诱导了先前未知的不同于凋亡和铁死亡的细胞死亡形式。我们将此细胞死亡形式命名为二硫化死亡。化学蛋白质组学和细胞生物学分析表明，在SLC7A11高表达细胞中，葡萄糖饥饿状态能以SLC7A11为依赖导致肌动蛋白细胞骨架蛋白的异常二硫键形成和F-肌动蛋白塌陷。CRISPR筛选和功能研究进一步显示，WAVE调节复合物（促进肌动蛋白聚合和薄膜伸展形成）的失活能够抑制二硫化死亡，而Rac的常规激活能够促进二硫化死亡。此外，我们还证明葡萄糖转运抑制剂能够诱导SLC7A11高表达癌细胞的二硫化死亡，并抑制SLC7A11高表达肿瘤的生长。我们的结果揭示了肌动蛋白细胞骨架对于二硫化压力的敏感性介导了二硫化死亡，并提出了通过靶向二硫化死亡以治疗癌症的治疗策略。 © 2023. 作者和Springer Nature Limited在独家许可下发表。

SLC7A11-mediated cystine uptake suppresses ferroptosis yet promotes cell death under glucose starvation; the nature of the latter cell death remains unknown. Here we show that aberrant accumulation of intracellular disulfides in SLC7A11high cells under glucose starvation induces a previously uncharacterized form of cell death distinct from apoptosis and ferroptosis. We term this cell death disulfidptosis. Chemical proteomics and cell biological analyses showed that glucose starvation in SLC7A11high cells induces aberrant disulfide bonds in actin cytoskeleton proteins and F-actin collapse in a SLC7A11-dependent manner. CRISPR screens and functional studies revealed that inactivation of the WAVE regulatory complex (which promotes actin polymerization and lamellipodia formation) suppresses disulfidptosis, whereas constitutive activation of Rac promotes disulfidptosis. We further show that glucose transporter inhibitors induce disulfidptosis in SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results reveal that the susceptibility of the actin cytoskeleton to disulfide stress mediates disulfidptosis and suggest a therapeutic strategy to target disulfidptosis in cancer treatment.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.