Research progress and potential therapeutic targets of a novel disulfide stress-driven cell death-disulfidptosis in gynecological tumors and other gynecological disorders.

Disulfidptosis is a novel Nicotinamide Adenine Dinucleotide Phosphate (NADPH) deficiency-driven cell death pathway characterized by cystine overload and aberrant disulfide bond formation in actin cytoskeletal proteins, distinct from apoptosis, ferroptosis, and other programmed cell death modalities. In gynecological tumors (ovarian, cervical, and endometrial cancers), this process is orchestrated by dysregulated SLC7A11 expression, impaired thioredoxin system function, and Rac-WRC-Arp2/3-mediated actin network collapse. Bioinformatic analyses of The Cancer Genome Atlas (TCGA)/Gene Expression Omnibus (GEO) datasets have revealed that disulfidptosis-related genes (e.g., SLC7A11, GYS1, NCKAP1) and lncRNAs (e.g., PRDX6-AS1, EMSLR) correlate with patient prognosis, chemoresistance, and tumor immune microenvironment (TME) remodeling. Therapeutic strategies to induce disulfidptosis include glucose deprivation to limit NADPH supply, inhibition of NADPH-generating enzymes (e.g., G6PD inhibition), and nanodelivery systems (e.g., FeOOH@Fe-Ap@Au) that synchronize disulfidptosis with ferroptosis. Preliminary evidence proposes that disulfidptosis inducers may synergize with immune checkpoint inhibitors (ICIs) through TME modulation, though experimental validation remains ongoing. Beyond malignancies, disulfidptosis-related pathways have been implicated in endometriosis, where disulfidptosis-related genes (DRGs; e.g., PDLIM1, ACTB) regulate ectopic lesion progression via immune-metabolic crosstalk. This review comprehensively summarizes the molecular mechanisms, disease associations, and translational potential of disulfidptosis in gynecological disorders, proposing targeted therapeutic paradigms and future research directions.