A novel lncPEAN inhibits the proliferation, invasion and migration of trophoblasts via WDR74/TGF-β1/Smad pathway.

Preeclampsia is believed to result from impaired placentation caused by insufficient trophoblast invasion, which leads to defective remodeling of uterine spiral arteries and inadequate uteroplacental angiogenesis. However, the underlying molecular mechanisms remain incompletely understood. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of placental biology and preeclampsia pathogenesis. Through RNA sequencing (RNA-seq) of placental tissues from preeclamptic and normal pregnancies, we identified a preeclampsia-associated lncRNA designated lncPEAN, which was significantly upregulated in both placental tissues and the peripheral blood of preeclamptic patients. Receiver operating characteristic (ROC) analysis demonstrated that lncPEAN distinguished preeclamptic from normal pregnancies with areas under the curve (AUCs) of 0.703 (placental tissue) and 0.893 (plasma). Functional overexpression and knockdown studies demonstrated that lncPEAN potently suppressed the proliferation, invasion, and migration of trophoblasts under hypoxic conditions. In vivo, silencing of lncPEAN mitigated the elevations in blood pressure and urinary protein levels and increased placental and fetal weights. Mechanistically, nuclear-localized lncPEAN directly bound to the WDR74 promoter and selectively enhanced H3K27ac deposition, thereby transcriptionally activating WDR74. Activated WDR74 subsequently augmented TGF-β1 expression and promoted Smad2/3 phosphorylation. Rescue experiments demonstrated that WDR74 knockdown or treatment with the TGF-β receptor inhibitor LY2109761 reversed lncPEAN-mediated suppression of trophoblast proliferation, invasion, and migration. Collectively, these findings indicate that lncPEAN silencing alleviates preeclampsia progression and rescues the dysfunctional trophoblast phenotype by targeting the WDR74/TGF-β1/Smad axis, highlighting its potential as a diagnostic biomarker for the onset of preeclampsia.