Iron-catalyzed oxidative stress reveals an exposome-related ferroptosis-resistant karyomegalic niche in BRCA1-linked renal carcinogenesis.

Early cancer initiation under chronic oxidative stress requires the survival of epithelial cells that should otherwise be eliminated by regulated cell death. However, the spatial and morphological identity of such stress-adapted cells remains poorly defined. Here, we integrated Xenium single-cell spatial transcriptomics, quantitative nuclear morphometrics, mitochondrial analyses, and human cancer datasets to investigate iron-driven renal carcinogenesis in Brca1(L63X/+) rats. Ferric nitrilotriacetate exposure induced dynamic remodeling of proximal tubular epithelium, characterized by loss of homeostatic transport and mitochondrial programs, and activation of Myc, Met, Lcn2, Anxa2 and iron-handling genes. BRCA1 haploinsufficiency expanded a karyomegalic proximal tubular state associated with mitochondrial dysfunction, chromatin hyperchromasia, nuclear remodeling, and ferroptosis-resistant transcriptional features. 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.