Integrative bioinformatics analysis identifies placental senescence-associated signatures in early-onset preeclampsia.

Background: Early-onset preeclampsia (EOPE) is a severe hypertensive disorder of pregnancy associated with preterm delivery and maternal multi-organ dysfunction. Although placental senescence and immune dysregulation have been implicated in EOPE, the expression profile of senescence-related genes(SRGs) and their mechanistic roles in disease progression remain unclear. Methods: Multiple placental bulk RNA-seq datasets were integrated to identify senescence-related differentially expressed genes in EOPE. Weighted gene co-expression network analysis (WGCNA) and multiple machine learning algorithms were used to identify hub genes. Single-cell RNA sequencing was further applied to define the cellular expression patterns of hub genes and characterize senescence-associated changes in EOPE. Key findings were subsequently validated in clinical placental specimens using molecular and functional experiments. Results: A total of 44 senescence-related differentially expressed genes were identified in EOPE placentas and were mainly enriched in cell proliferation-related pathways. LEP, ENG, MIF, and CYBB were identified as hub genes and were predominantly expressed in trophoblasts and immune cells. Single-cell analysis showed that senescence-associated activity was primarily enriched in the trophoblast lineage and further implicated LEP in syncytiotrophoblast (SCT) senescence and SCT secretory dysfunction, suggesting a role in EOPE pathogenesis. Conclusions: Our findings suggest that EOPE is closely related to placental senescence. Deeper investigation of SRGs and pathways may aid early diagnosis and clarify the molecular basis of EOPE.