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

INTRODUCTION

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.

HYPOTHESIS: 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.

DISCUSSION: 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.