Disulfidptosis, a newly identified form of cell death, holds significant biological relevance; however, its role in cardiovascular diseases remains poorly characterized. To investigate this, disulfide bond formation was evaluated using non-reducing Western blot, while cytoskeletal alterations were assessed via phalloidin staining. In vivo experiments using a rat model of myocardial infarction (MI) and in vitro experiments using H9c2 cardiomyocytes subjected to oxygen‑glucose deprivation (OGD) both demonstrated upregulation of SLC7A11, NADPH depletion, and cystine accumulation under OGD or MI conditions. Notably, increased disulfide bonds in actin cytoskeletal proteins were observed, leading to cytoskeletal collapse. Inhibition of SLC7A11 rescued disulfidptosis across all models. Cellular knockdown of Nckap1 (a core component of the Rac1-WRC-Arp2/3 pathway) suppressed disulfidptosis, whereas overexpression of Rac1, Nckap1, or Wave2 promoted it. Spatial transcriptomic analysis of human infarcted myocardium further validated the concurrent upregulation of SLC7A11 and Rac1-WRC-Arp2/3 pathway components. Collectively, these findings indicate that MI induces disulfidptosis—a novel cell death modality mediated by activation of the SLC7A11 and Rac1-WRC-Arp2/3 signaling pathways. Disulfidptosis is involved in myocardial infarction injury and is driven by SLC7A11-dependent cystine overload and Rac1-WRC-Arp2/3-mediated actin cytoskeletal collapse.
Shao et al. (Mon,) studied this question.
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