Disulfidptosis-Related Genes Comprise Two Functionally Distinct, Transcriptionally Uncoupled Subsets with Complementary Prognostic Associations: An Integrated Pan-Cancer Analysis of TCGA Data

Disulfidptosis is a regulated form of cell death that arises from NADPH depletion and disulfide stress on the actin cytoskeleton in cells with high SLC7A11. Scores built from disulfidptosis-related genes (DRGs) are increasingly put forward as prognostic markers, yet their internal structure and metabolic context have remained poorly defined. We examined 24 DRGs across 10,242 primary tumours (33 TCGA cancer types) and 722 normal tissues, drawing on survival, purity and genomic data. SLC7A11 was up-regulated in 14 of 18 cancers, while the majority of cytoskeletal DRGs sat at lower levels in tumours. The DRG score showed a heterogeneous pooled link to shorter overall survival (HR per SD 1.15, 95% CI 1.06–1.25; prediction interval 0.78–1.70) and stayed associated after adjustment for available clinical covariates and purity in six cancers (FDR < 0.05): adverse in five, among them lower-grade glioma (HR 1.68; attenuated to 1.24, p = 0.046, after adjustment for IDH and 1p/19q status, grade and purity) and mesothelioma, and protective in clear-cell renal carcinoma. The predefined core and cytoskeleton subsets were almost uncorrelated (median ρ = −0.04): SLC7A11 expression tracked pentose phosphate/NADPH genes independently of purity (median ρ = 0.32), whereas the cytoskeleton subset ran opposite to oxidative phosphorylation genes. After adjustment for NRF2 target expression, however, SLC7A11 was not more strongly coupled to core PPP enzyme genes than expression-matched random genes. In joint models, each subset proved independently prognostic, but in different cancers. The composite score was prognostic in more cancer types than random gene sets of equal size (9 vs. 3; p = 0.04), whereas in the four cancers with robust models, DRG-based LASSO-Cox models performed no better than models built from random 24-gene sets. DRG scores are better decomposed than read as a single disulfidptosis axis.