Sorting nexin 9 (SNX9) dysregulation impairs decidualization and correlates with severe preeclampsia

In brief: SNX9 is first shown to be essential for normal decidualization. Its downregulation in decidual tissue impairs trophoblast invasion and may underlie severe preeclampsia, revealing a new molecular pathway in this poorly understood dangerous pregnancy complication. Abstract: Preeclampsia (PE) is a gestational hypertension disorder emerging after 20 weeks of pregnancy, complicating 5%-8% of pregnancies and representing a leading cause of maternal-fetal morbidity and mortality. Despite its clinical significance, the etiology and pathogenesis of PE remain obscure. Sorting nexin 9 (SNX9), a key regulator of intracellular trafficking and endomembrane dynamics, has been poorly explored in reproductive physiology. This study investigates the role of SNX9 in PE, demonstrating significant downregulation of SNX9 in decidual tissues from preeclamptic patients. In vitro decidualization models showed that SNX9 expression correlated with decidualization progression, as evidenced by upregulation of decidual markers (IGFBP1, PRL), while SNX9 knockdown impaired decidualization. Transwell assays revealed that aberrant SNX9 expression restricted trophoblast invasion into endometrial stromal cells. In pregnant mice, SNX9 expression in decidual tissues positively correlated with decidualization regulators (Wnt4, Bmp2) and markers (Prl8a2, Dtprp). Consistent expression patterns were observed in pseudopregnant mice after artificial decidualization induction, excluding embryonic influences. Collectively, these findings establish SNX9 as essential for normal decidualization, with dysregulated SNX9 potentially contributing to PE pathogenesis. This study uncovers a novel link between endomembrane dynamics and PE, providing insights into its molecular mechanisms.