Mechanism, biomarkers, and therapeutic significance of trophoblastic ferroptosis in recurrent miscarriage

作者：Liu X, Su F · 发表于：Tissue & cell · 年份：2026 · DOI：10.1016/j.tice.2026.103543 · 研究领域：Ferroptosis、Trophoblasts、Biomarkers、Abortion, Habitual、Humans、Female、Pregnancy、Animals、Iron

Recurrent miscarriage (RM), affecting 1-2% of reproductive-age women, poses significant physical, psychological, and economic burdens, with up to 50% of cases unexplained. This review elucidates the role of trophoblastic ferroptosis an iron-dependent regulated cell death (RCD) pathway characterized by lipid peroxidation, GSH depletion, and mitochondrial dysfunction-in RM pathogenesis. At the maternal-fetal interface, iron homeostasis is tightly regulated via transporters like transferrin receptor 1 (TfR1), divalent metal transporter 1 (DMT1), and FPN, but dysregulation leads to local iron overload in trophoblasts, exacerbated by hypoxia, inflammation, and metabolic factors. Canonical mechanisms involve GPX4 inactivation, ACSL4-mediated lipid peroxidation, and ROS accumulation via Fenton reactions. Trophoblast-specific adaptations include HIF-1α-driven ferritinophagy through the lnc-HZ06/HIF1α-SUMO/NCOA4 axis, heme dysmetabolism, and cytokine amplification (e.g., TNF-α/IL-1β). Endocrine triggers like progesterone deficiency and maternal obesity further sensitize cells to ferroptosis. Biomarkers encompass circulating (e.g., elevated ferritin, MDA; reduced GPX4), placental (e.g., upregulated ACSL4, mitochondrial shrinkage), and omics-derived signatures (e.g., transcriptomic hubs like TP53, lipidomic Ox-PEs). Clinical evidence from cohorts and experimental models (e.g., hypoxia-induced mouse abortions) links ferroptosis to trophoblast invasion failure and immune dysregulation (e....