Maternal causation of early-onset pre-eclampsia: excessive endometrial gland-derived apolipoprotein D induces placental ferroptosis and developmental abnormalities

Abstract Background Early-onset pre-eclampsia (ePE) is a severe pregnancy complication characterized by dysregulated trophoblast functions and impaired placentation during early pregnancy, leading to substantial maternal and fetal morbidity. While circumstantial evidence indicates defective secretion from endometrial glands impairs placental development, direct evidence linking maternal glandular dysfunction to ePE pathogenesis remains elusive. Methods We established endometrial glandular organoids from women with ePE and healthy pregnancies, analyzing their secretomes by iTRAQ-based proteomics, RNAseq, and spatial transcriptomics. Functional effects of organoid secretomes on trophoblasts were examined in vitro. An endometrial-specific apolipoprotein D (APOD) knock-in mouse model was studied in vivo. APOD levels in first-trimester serum samples from women who later developed ePE were compared to healthy pregnancies. Results Secretomes from ePE derived endometrial organoids impeded spiral artery remodeling. Multiomic analyses revealed increased APOD production in both ePE organoids and decidual tissues. APOD overexpression disrupted trophoblast functions and endothelial vascular remodeling in vitro, and recapitulated ePE phenotypes in an APOD knock-in mouse model through PI3K/Akt-mediated placental ferroptosis and potential ER stress induction. Ferroptosis inhibition with Fer-1 rescued placental defects and PE symptoms in APOD knock-in mice. Elevated APOD levels in first-trimester serum samples from women who later developed ePE suggest its potential as an early biomarker. Conclusion This study provides the first direct evidence linking dysregulated endometrial gland function to defective placentation and ePE. APOD was identified as a crucial endometrial gland-secreted factor contributing to ePE, suggesting its potential as an early biomarker and therapeutic target.