Iron Overload-Induced Ferroptosis Drives Placental Dysfunction in Preeclampsia

BACKGROUND: Preeclampsia, a life-threatening hypertensive disorder of pregnancy, has been linked to iron dysregulation, though mechanistic insights remain limited. METHODS: We integrated clinical data, a reduced uterine perfusion pressure mouse model, in vitro trophoblast cell experiments, and placental organoids derived from patients with preeclampsia. Iron metabolism was assessed via mass spectrometry, quantitative polymerase chain reaction, Peris’ Prussian blue staining and immunohistochemistry. Ferroptosis markers and iron transporters were analyzed. Interventions included the iron chelator deferoxamine, antioxidant MitoQ, ferroptosis inhibitor Fer-1 (ferrostatin-1), and the apoptosis inhibitor Z-VAD. RESULTS: Patients with preeclampsia exhibited elevated hemoglobin, ferritin, and serum iron levels from the second trimester, alongside placental iron overload. Single-cell/nucleus RNA sequencing revealed dysregulated iron transporters ( TFRC ↑, DMT1 ↑, FPN ↓) in preeclampsia trophoblasts. Iron overload induced ferroptosis and apoptosis in trophoblasts, evidenced by increased lipid peroxidation (4HNE↑, Gpx4↓), ROS, Tunnel staining positive and cell death, while suppressing PlGF and progesterone secretion. Both deferoxamine and MitoQ rescued these effects in vitro (similar to Ferr-1) and in preeclampsia-derived organoids. The reduced uterine perfusion pressure model confirmed the preservation of iron dyshomeostasis and ferroptosis in preeclamptic placentas, while oral administration of MitoQ was found to reduce 4-hydroxynonenal and malondialdehyde expression in placenta. CONCLUSIONS: Our findings reveal that iron overload and subsequent ferroptosis contribute to placental damage in preeclampsia, suggesting that iron metabolism dysregulation is a critical feature of the disease. This highlights the need to reevaluate iron supplementation protocols in high-risk pregnancies and to consider individualized iron management strategies that balance maternal-fetal iron requirements while minimizing oxidative stress.