Enhancing cancer susceptibility to disulfidptosis by inducing cell cycle arrest and impairing DNA repair.

Disulfidptosis-a regulated cell death caused by disulfide stress under glucose starvation and high SLC7A11-offers a potential cancer vulnerability, but its regulatory landscape and therapeutic tractability remain unclear. We sought to (i) map disulfidptosis susceptibility across cancers, (ii) define associated pathways and regulators, and (iii) test whether targeting these pathways enhances disulfidptosis to improve antitumor efficacy. Methods: We curated 43 core regulators to compute the disulfidptosis score (D-score) across ~10,000 TCGA tumors, benchmarked with glucose-starvation datasets. Correlation screening yielded 506 candidate regulators, integrated into a refined score (D-score+). We associated D-score+ with hallmark pathways, genomic instability and DNA-repair signatures. Experimental validation used glucose-deprivation models, non-reducing immunoblotting and immunofluorescence of cytoskeletal proteins, CRISPR perturbations, and pharmacologic combinations with cell-cycle arrest agents and PARP inhibitors. Public clinical and drug-response cohorts supported translational analyses. Results: D-score tracked experimental triggers (glucose starvation) and revealed cancer-type-specific prognostic patterns. D-score+ positively correlated with cell-cycle programs (e.g., G2/M checkpoint, spindle) and negatively with DNA-repair activity, while aligning with multiple genomic-instability signatures. Beyond F-actin, tubulin exhibited disulfide-dependent mobility shifts and microtubule disassembly. Combining disulfidptosis with cell-cycle arrest drugs synergistically increased cell death across models, with dose-responsive effects and cross-cancer activity. PARP inhibition synergized with disulfidptosis in multiple lines, and higher susceptibility tracked with PARP-inhibitor sensitivity datasets; CRISPR loss of ATM or FANCD2 further sensitized cells. D-score+ was lower in metastatic versus primary tumors and inversely related to EMT in select cancers; glucose starvation impaired migration in wound-healing assays. Conclusions: Inducing cell-cycle arrest and compromising DNA repair enhances cancer susceptibility to disulfidptosis, in part via redox-dependent disruption of actin and microtubules. D-score/D-score+ provide quantitative biomarkers to stratify tumors for combination strategies pairing disulfidptosis induction with cell-cycle inhibitors or PARP inhibitors. These findings nominate disulfidptosis-related pathways as actionable targets and support integrating disulfidptosis profiling into precision oncology, warranting in vivo and clinical validation.