Mechanistic insights into disulfidptosis in cancer and therapeutic opportunities

Cancer cells display highly adaptive characteristics under nutrient-deficient and oxidative stressed conditions. Disulfidptosis has recently been recognized as a novel, forcefully mediated form of cell death, specifically induced by NADPH depletion under glucose deprivation, pathological disulfide bond buildup, and disastrous cytoskeletal disruption. In contrast to traditional cell death modes, including signaling cascade-mediated cell death and lipid peroxidation-mediated ferroptosis, disulfidptosis is mediated by structural redox instability, thus ascribing a central role to the cytoskeletal architecture as a biosensor against metabolic insults. In this review, we summarize the recent mechanistic, transcriptome, and functional evidence establishing disulfidptosis as a broadly applicable form of cell death within cancers. Furthermore, we define the molecular mechanism, distinguish disulfidptosis by transcriptional parsing with cell deaths such as apoptosis, ferroptosis, necroptosis, and cuproptosis, as well as explore tumor type specificity governed by glucose dependence, redox capabilities, and cytoskeletal dynamics. Using an integrative transcriptome and experimental approach, we identify a consistent fragility within SLC7A11-high, glucose-dependent cancers as a reproducible targetable feature, as well as review pharmacologically activatable platforms, nanotechnology, and natural/bioactive compounds to modulate the disulfide-NADPH nexus to specifically trigger cytoskeletal disruption. Finally, challenges to disulfidptosis as a translationally tractable cell death are addressed within biomarker establishment and selectivity towards targetable malignancy.