The placenta, a vital organ for both the fetus and the mother, participates in mediating their health [1]. The formation of the placenta relies on the normal physiological function of trophoblast cells. Human placental development originates from the trophectoderm of the blastocyst, which consists of three main trophoblast subpopulations: cytotrophoblast (CTB), extravillous cytotrophoblast (EVT), and syncytiotrophoblast (STB). As trophoblasts differentiate, CTB can either gradually merge into STB located outside the placental villi, or undergo epithelial-to-mesenchymal transition to form extravillous trophoblasts (EVT) [2]. Extravillous trophoblasts establish anchoring villi and invade the uterine spiral arteries, transforming them into vessels with 'low resistance and high flow, which ensures a sufficient supply of nutrients to the fetus [3,4]. Pre-eclampsia(PE) is new onset hypertension after 20 weeks of gestation, associated with proteinuria OR organ dysfunction [5]. Insufficient trophoblast invasion and abnormal uterine spiral artery remodeling are considered important causes of preeclampsia [6].

Cholesterol plays a critical role in the formation of cell membranes and the synthesis of numerous hormones, and it is metabolized into oxysterols [7]. Oxysterols are involved in various aspects of lipid metabolism and have been linked to atherosclerosis, inflammation, cell apoptosis, and immune suppression [8,9]. 27-hydroxycholesterol (27-HC) is the most abundant oxysterol in human peripheral blood [10], with a concentration of 0.3–0.8 μM in healthy individuals, which rises with hypercholesterolemia [11]. The ubiquitous mitochondrial enzyme cholesterol 27-hydroxylase (CYP27A1) acts on cholesterol to produce 27-HC, which is then metabolized in the liver by oxysterol 7-alpha-hydroxylase (CYP7B1) [12]. Research has indicated that 27-HC is a natural ligand for the nuclear receptor LXR [13]. Upon activation, LXR regulates the expression of target genes by forming heterodimers with retinoid X receptor (RXR) and subsequently binding to LXR response elements in the promoter regions of target genes [14]. LXR transcriptionally activates target genes such as ABCA1 and ABCG1, thereby participating in the regulation of dynamic lipid and cholesterol balance [15]. The two LXR subtypes, LXRα (NR1H3) and LXRβ (NR1H2), have been found to be expressed in the human placenta at 6 weeks of pregnancy, where they are involved in the regulation of fatty acid and cholesterol transport in trophoblast cells [16]. Existing research has established a close association between 27-HC and the invasive and migratory capabilities of various tumor cells, including breast cancer and glioblastoma [10]. Hiten D. Mistry and colleagues observed elevated levels of 27-HC in the peripheral blood serum of patients with pre-eclampsia (PE) [17]. However, the specific mechanism by which 27-HC is involved in the pathogenesis of PE has not been reported.

In this study, compared to the control samples, the serum levels of 27-HC and the placental expression of CYP27A1 were elevated in clinical samples of PE. In vitro experiments showed that high concentrations of 27-HC inhibited the invasive and migratory abilities of trophoblast cells, and after knocking down LXR, the inhibitory effect of 27-HC was weakened. Finally, we established a mouse model of PE and found that the levels of 27-HC in the serum of PE mice increased compared to the control group, and the protein expression of CYP27A1 and LXR in the placenta increased as well. Therefore, we believe that 27-HC inhibits the invasive and migratory functions of trophoblast cells by activating LXR, leading to the occurrence of PE.