Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis

Xiaoguang Liu, Litong Nie, Yilei Zhang, Yuelong Yan, Chao Wang, Medina Colic, Kellen Olszewski, Amber Horbath, Xiong Chen, Guang Lei, Chao Mao, Shiqi Wu, Li Zhuang, Masha V. Poyurovsky, M. James You, Traver Hart, Daniel D. Billadeau, Junjie Chen, Boyi Gan

Research output: Contribution to journalArticlepeer-review

300 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)404-414
Number of pages11
JournalNature cell biology
Issue number3
StatePublished - Mar 2023
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cell Biology


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