Beyond biochemical cascades: the biophysical execution of disulfidptosis via actin network collapse.

The discovery of disulfidptosis has identified a distinct form of regulated cell death in which metabolic redox failure is translated into biophysical disruption of the actin cytoskeleton. This review synthesizes current evidence on the molecular machinery of actin remodeling under disulfide stress, with particular emphasis on the Rac1-WRC-Arp2/3 signaling axis and other actin-regulatory nodes. Mechanistically, disulfidptosis can be conceptualized as a redox-to-mechanics transition. In SLC7A11-high cells, glucose deprivation limits pentose phosphate pathway-derived NADPH production and weakens NADPH-dependent reducing systems, while continued cystine uptake promotes cystine accumulation and disulfide stress. This redox imbalance favors disulfide bond formation in actin cytoskeleton-associated proteins, disrupts actin filament turnover and network organization, and ultimately contributes to actin cytoskeleton collapse and disulfidptosis. Beyond SLC7A11-high cancer models, emerging bioinformatic and experimental observations suggest that related redox-cytoskeletal vulnerabilities may also be relevant to selected ischemia-reperfusion and neurodegenerative contexts, although direct evidence for bona fide disulfidptosis in these settings remains limited. Finally, this review discusses key unresolved questions and future directions, including residue-specific mapping of actin modifications, biomarker development, model validation beyond cancer cells, and therapeutic strategies aimed at preserving reducing capacity or cytoskeletal stability.