ZFP36 inhibits trophoblast ferroptosis and attenuates preeclampsia development by promoting NCOA4 mRNA degradation and suppressing ferritinophagy.

Preeclampsia (PE), a pregnancy-specific disorder characterized by placental dysfunction and severe maternal-fetal complications, involves ferroptosis-an iron-dependent cell death driven by oxidative stress and lipid peroxidation. This study investigated the role of zinc-finger protein 36 (ZFP36) in regulating ferroptosis in trophoblast cells and its underlying mechanisms.In vitro, hypoxia/reoxygenation was applied to human trophoblast HTR-8/SVneo cells to model ischemic injury. ZFP36 was found to inhibit oxidative stress and ferroptosis by suppressing nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Mechanistically, ZFP36 binds to the 3' untranslated regions (3'UTRs) ofNCOA4mRNA, promoting its degradation and thereby attenuating ferritinophagy.In vivo, lentiviral overexpression of ZFP36 in a rat model of PE (induced by reduced uteroplacental perfusion pressure) alleviated clinical symptoms and reduced NCOA4-mediated ferroptosis. Collectively, these results demonstrate that ZFP36 regulates ferroptosis by modulating NCOA4-dependent ferritinophagy, offering a potential therapeutic strategy for PE through targeting ferroptosis.