The crosstalk between ferroptosis and cellular senescence in gestational diabetes mellitus: from iron dyshomeostasis to trophoblast dysfunction

Gestational diabetes mellitus (GDM) comprises heterogeneous placental phenotypes that include fetal overgrowth, large-for-gestational-age birth, and fetal growth restriction (FGR). We propose a testable endotype model in which maternal hyperglycemia, advanced glycation end products, diabetic dyslipidemia, altered polyunsaturated fatty-acid delivery, gestational iron exposure, and the physiologic fall in hepcidin converge on a redox-stressed trophoblast microenvironment. In proliferative cytotrophoblasts and extravillous trophoblasts, the relative reserve of GPX4 and FSP1/CoQ10, ACSL4-dependent PUFA-phospholipid loading, proliferative status, and insult intensity and duration are predicted to determine whether cells undergo ferroptosis, enter senescence, or occupy an intermediate state. We further propose an asymmetric crosstalk model: senescent trophoblasts are relatively ferroptosis-resistant, retain iron, and act in trans through SASP factors, reactive oxygen species, and oxidized lipids on ferroptosis-susceptible neighboring cells. The model predicts a gestational-age-dependent window in which physiologic senescence accumulates and its paracrine effects become injurious. Ferrostatin-1 or liproxstatin-1 should rescue lipid-peroxidation-driven death in susceptible cells without reversing senescence in iron-retaining cells. The model is GDM-specific in its initiating inputs and gestational context, but the reciprocal links remain hypotheses rather than established facts. It predicts that an injury-dominant placental endotype will show spatially adjacent iron-retaining senescence-like cells and lipid-peroxidation-driven cell death, impaired nutrient transport, and FGR, whereas compensatory transport and villous expansion may produce large-for-gestational-age phenotypes in other GDM placentas. We outline experiments that could support or falsify this model and define pregnancy-specific safety constraints for therapeutic testing.