KDM4C regulates trophoblast proliferation and migration in preeclampsia via the NFATc4/Wnt pathway.

Preeclampsia (PE), a serious pregnancy complication characterized by hypertension and organ dysfunction, is associated with impaired trophoblast function. While epigenetic dysregulation, including histone modification, is implicated in its pathogenesis, the role of lysine-specific demethylase 4C (KDM4C) in PE remains unclear. This study revealed significant upregulation of KDM4C in PE placental tissues and hypoxic HTR-8/SVneo cells, assessed by qRT-PCR, immunohistochemistry (IHC), and Western blot. Validation experiments in an L-NAME-induced PE rat model corroborated these findings. Functional assays demonstrated that KDM4C overexpression suppressed trophoblast proliferation and migration. Mechanistically, KDM4C reduced H3K9me3 repression at the nuclear factor of activated T-cells, cytoplasmic 4 (NFATc4) locus, increasing NFATc4 expression. NFATc4 inhibited β-catenin nuclear translocation by binding Dishevelled (Dvl), disrupting Wnt/β-catenin signaling. Collectively, our results identify KDM4C as a key epigenetic regulator driving trophoblast dysfunction in PE through the NFATc4/Wnt pathway, positioning KDM4C as a promising therapeutic target.