Work

ULK2 deficiency stratifies autophagy-driven molecular subtypes and exacerbates trophoblasts apoptosis in preeclampsia

Year: 2025

Type: article

Abstract: Preeclampsia (PE), a placenta-originated hypertensive disorder of pregnancy, lacks targeted therapies despite its significant contribution to maternal and fetal morbidity. Emerging evidence implicates autophagy dysregulation in PE pathogenesis, though its molecular heterogeneity remains unexplored. This study aims to investigate autophagy-related molecular subtypes in PE and identify ULK2 key regulators linking autophagic imbalance to placental dysfunction. Placental transcriptomic datasets were analyzed to identify autophagy-related differentially expressed genes (ARGs). Unsupervised consensus clustering stratified 80 PE patients into molecular subtypes. Protein-protein interaction (PPI) networks, machine learning algorithms, and functional enrichment analyses were employed to delineate hub genes and pathways. ULK2's role was validated via qRT-PCR, shRNA knockdown in HTR8/SVneo trophoblasts, and immunofluorescence. A murine PE model was established using the ULK1/2 inhibitor MRT68921 to assess systolic blood pressure, fetal growth, and placental autophagy-apoptosis dynamics. Unsupervised clustering of 45 ARGs classified PE patients into ULK2 low and ULK2 high subtypes. The ULK2 low subtype exhibited severe clinical features: elevated preterm delivery, systolic hypertension, HELLP syndrome incidence and increased proteinuria. ULK2-kncokdown trophoblasts showed impaired autophagy and upregulated apoptosis. Six hub genes correlated with disease severity and inversely with ULK2 expression. In mice, ULK2 inhibition induced PE-like phenotypes: sustained hypertension, fetal growth restriction and severe proteinuria. ULK2 deficiency disrupts trophoblast homeostasis, driving placental dysfunction and severe clinical outcomes. The ULK2 low subtype highlights autophagy heterogeneity in PE. While pharmacological ULK2 inhibition recapitulates PE in mice, limitations include sample size and MRT68921's dual ULK1/2 activity. Our findings propose ULK2 agonism as novel therapeutic strategies. • Molecular subtyping reveals ULK2 low as a high-risk autophagy-dysregulated phenotype. • Six-gene biomarker panel predicts severe PE and inversely correlates with ULK2. • ULK2 deficiency drives trophoblast apoptosis via autophagic flux impairment. • Pharmacological ULK2 inhibition recapitulates PE in Mice, validating therapeutic potential.

Source: Placenta

DOI: 10.1016/j.placenta.2025.04.015