A coupled iron-hypoxia selection model for the evolution of endometriosis-associated ovarian clear cell carcinoma

Ovarian clear cell carcinoma (OCCC) frequently arises in association with endometriosis and is characterized by iron-rich oxidative stress, hypoxia-responsive metabolic reprogramming, glycogen accumulation, and alterations in ferroptosis-regulatory pathways. Interactions among hypoxia, iron metabolism, oxidative stress, and ferroptosis are increasingly recognized, but their role during precursor evolution remains uncertain.

We propose that chronic iron-rich oxidative stress and a hypoxic microenvironment may jointly alter the relative fitness of epithelial cells during the endometriosis-to-OCCC transition. Repeated exposure may create a putative ferroptosis-related selection filter that preferentially removes susceptible cells while enriching less-susceptible cellular subpopulations capable of sustained survival. Here, ferroptosis tolerance denotes relative survival under chronic or sublethal ferroptosis-related stress and does not imply experimentally demonstrated resistance; broader oxidative-stress adaptation alone is insufficient to establish it. Surviving populations may acquire an adaptive iron-handling state that constrains the metabolically available labile iron pool despite an iron-rich extracellular environment through changes in iron uptake, ferritin-mediated sequestration and turnover, mitochondrial utilization, cellular export, or extracellular-vesicle-mediated ferritin disposal. These mechanisms may cooperate with HIF-1α/SLC1A1-associated adaptation and NRF2/SLC7A11/GPX4/glutathione pathways. Loss-of-function alteration of ARID1A may contribute to oncogenic evolution, while ARID1A deficiency may also modify redox and ferroptotic vulnerability and thereby the intensity of selection.

The novelty of this framework lies not in any single molecular interaction, but in applying interconnected iron, hypoxia, redox, and ferroptosis biology to an evolutionary selection model across the endometriosis-atypical endometriosis-OCCC continuum. The model predicts coordinated stress and iron-handling adaptations in precursor lesions, reproducible changes in population composition after repeated sublethal iron-hypoxia exposure, and, as a distinct outcome, durable phenotypic adaptation after washout. These predictions can be tested through cyst-fluid analysis, spatial profiling, and repeated-exposure, washout, rechallenge, and lineage-tracing experiments. The framework is a falsifiable hypothesis that may be supported, narrowed, reformulated, or rejected experimentally.