Comparative analysis of lipid metabolism in trophoblast subpopulations in preeclampsia and in vitro hypoxia model

Preeclampsia is a leading cause of maternal and perinatal morbidity associated with systemic lipid metabolism disturbances, yet the underlying molecular mechanisms remain incompletely understood. In this study, we integrated single-cell RNA-seq data from preeclamptic placentas with an in vitro hypoxia model to analyze gene expression changes across distinct trophoblast subpopulations. While all trophoblast lineages exhibited hypoxia-driven metabolic reprogramming, the response was highly cell-type specific. In the syncytiotrophoblast (SCT), the primary maternal-fetal barrier, preeclampsia was associated with a significant downregulation of LDLR and cholesterol biosynthesis genes (OR = 4.991, p = 6.30e-04). Concurrently, we observed increased expression of genes governing transcytosis (<i>SCARB1</i>, <i>CAV1</i>). In contrast, the extravillous trophoblast (EVT) displayed a divergent adaptive response, characterized by elevated LDLR expression and downregulated cholesterol biosynthesis. <i>In vitro</i> hypoxia modeling in BeWo b30 cells recapitulated the SCT-specific phenotype and identified a potential regulatory mechanism: a fivefold increase in <i>PCSK9</i> expression (padj = 3.53e-10) and a 1.5-fold decrease in <i>SNX17</i> (padj = 1.76e-04)-key regulators that limit lipoprotein receptor recycling. This was accompanied by the suppression of lipid biosynthesis genes and the transcriptional activation of pathways associated with transcytosis and cholesterol efflux. Collectively, these results confirm the pivotal role of hypoxic stress in disrupting placental lipid metabolism and reveal a subpopulation-specific transcriptional program in preeclampsia-a shift from endocytosis to transcytosis-that likely serves as a compensatory mechanism to ensure fetal lipid supply under conditions of limited availability.