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 SLC7A11^high 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 SLC7A11^high 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 SLC7A11^high cancer cells and suppress SLC7A11^high 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.

SLC7A11 介导的胱氨酸摄取抑制铁死亡，但在葡萄糖饥饿下促进细胞死亡；后者细胞死亡的性质仍然未知。^{在这里，我们发现，在葡萄糖饥饿下，SLC7A11 high}细胞中细胞内二硫化物的异常积累会诱导一种不同于细胞凋亡和铁死亡的先前未表征的细胞死亡形式。我们将这种细胞死亡称为二硫下垂症。化学蛋白质组学和细胞生物学分析表明，SLC7A11 ^high细胞中的葡萄糖饥饿会诱导肌动蛋白细胞骨架蛋白中的异常二硫键，并以 SLC7A11 依赖性方式导致 F-肌动蛋白崩溃。CRISPR 筛选和功能研究表明，WAVE 调节复合物（促进肌动蛋白聚合和片状伪足形成）的失活可抑制二硫下垂，而 Rac 的组成型激活可促进二硫下垂。我们进一步表明，葡萄糖转运蛋白抑制剂可诱导 SLC7A11^高癌细胞中的二硫下垂并抑制 SLC7A11^高肿瘤生长。我们的结果表明，肌动蛋白细胞骨架对二硫键应激的敏感性介导二硫键下垂，并提出了一种在癌症治疗中针对二硫键下垂的治疗策略。