Iron-Catalyzed Oxidative Stress Reveals an Exposome-Related Ferroptosis-Resistant Karyomegalic Niche in BRCA1-Linked Renal Carcinogenesis

Subclassification of karyomegalic cells identified distinct stress-adaptive populations, including a BRCA1-associated K2 state enriched for Myc/Met/Lcn2 signaling and preferentially embedded within a pro-oncogenic epithelial–stromal microenvironment. Of note, neighboring non-karyomegalic proximal tubular cells acquired related iron-handling and survival-biased programs, indicating that karyomegaly marks a broader pre-neoplastic field rather than an isolated abnormality.

Human TCGA renal cancer analyses and morphometric assessment of BRCA1-mutant breast tissue further supported the clinical relevance of karyomegaly-associated gene modules and nuclear remodeling. These findings define a spatially organized, ferroptosis-resistant karyomegalic niche as an early lesion in iron-driven carcinogenesis and establish quantitative nuclear morphology as a functional readout of exposome-related oxidative stress adaptation in genetically susceptible tissues.