Integrative oxidative stress-disulfidptosis analysis identifies NPR3 and ZNF366 as cell-type-associated candidate markers in clear cell renal cell carcinoma.

Authors

Ping Wang, Zhixuan Cai, Gaofeng Wu, Guangfeng Zhu

Published in

Frontiers in molecular biosciences. Volume 13. Pages 1912537. Epub Sep 23, 2026.

Abstract

Disulfidptosis is a regulated cell-death program that occurs in SLC7A11-high cells under glucose limitation, but its relationship with oxidative stress in clear cell renal cell carcinoma (ccRCC) remains unclear. We integrated 313 oxidative stress-related genes with 24 disulfidptosis-related genes in the original TCGA-KIRC analysis. Pearson screening (|r| ≥ 0.8 and nominal two-sided P < 0.05) identified 21 disulfidptosis-oxidative stress (DOS) genes, from which three reported DOS subtypes, 63 subtype-associated genes and a four-gene score comprising ZNF366, EMCN, GRIK3 and NPR3 were derived. In an updated GDC-derived TCGA-KIRC dataset, both k = 3 classifications showed method-dependent stability, with weaker stability for the available 58-of-63-gene solution. Outcome-blind centroid transfer assigned all 101 E-MTAB-1980 cases and reproduced several molecular and immune/stromal differences in GSE73731, although the hard clusters have not been independently validated for prognosis. In the atezolizumab-containing arms of IMmotion150, the within-cohort re-standardized four-gene score was lower in patients with clinical benefit and was associated with progression-free survival; the DOS21 module score was not associated with clinical benefit. The fixed four-gene score had modest internal discrimination (bootstrap optimism-corrected C-index, 0.697), and its transfer was sensitive to platform scaling and stage adjustment. Under the single 6-h glucose-deprivation condition, NPR3 and ZNF366 increased only in SLC7A11-high UMRC6 cells. Single-cell analyses in one VHL-related case and an independent 19-patient ccRCC cohort supported endothelial enrichment of ZNF366 and showed that NPR3 was not restricted to tumor cells. These findings identify NPR3 and ZNF366 as compartment-associated candidate markers but do not establish a functional role in disulfidptosis.

PMID:
42845728
Bibliographic data and abstract were imported from PubMed on 08 Oct 2026.

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