Impaired syncytin-1-CXCR4 crosstalk contributes to trophoblast migration defects in preeclampsia

Preeclampsia is a pregnancy-specific disorder characterized by de novo hypertension and proteinuria after 20 weeks of gestation, affecting 3-8% of pregnant women globally. Current management relies primarily on preventive strategies and symptomatic relief, with urgent delivery remaining the only definitive intervention. Syncytin-1, a human endogenous retroviral envelope protein, is implicated in preeclampsia pathogenesis via modulating trophoblast function and uterine spiral artery remodeling, though its precise molecular mechanisms remain unclear.

This study utilized transcriptome sequencing of syncytin-a conditional knockout mice, alongside String database analysis, ClusPro/GRAMM/HDOCK molecular docking, immunofluorescence co-localization, and co-immunoprecipitation to predict and validate Syncytin-1 interacting partners. Bioinformatics, western blotting, and RT-qPCR were applied to screen and confirm differentially expressed genes in preeclamptic cell models and placental tissues. HTR-8/SVneo cells were treated with si-ERVW-1, the CXCR4 inhibitor AMD3100, or the CXCR4 agonist NUCC390, followed by functional analyses.

We identified direct co-localization and interaction between Syncytin-1 and CXCR4 in HTR-8/SVneo cells. Downregulated expression of Syncytin-1 and key components of the CXCR4/GNAQ/CALM2/NFATC1 pathway was observed in preeclamptic cell models and placental tissues. In HTR-8/SVneo cells, si-ERVW-1 or AMD3100 treatment markedly reduced Syncytin-1 and CXCR4 signaling molecule expression (CXCR4, GNAQ, CALM2, NFATC1) and significantly suppressed cell migration and invasion effects reversed by NUCC390.

These findings suggest that Syncytin-1 downregulation may drive preeclampsia by targeting CXCR4 to inhibit the GNAQ/CALM2/NFATC1 pathway and reduce trophoblast migratory and invasive capacities.