DHODH regulates trophoblast fusion via IFITM-reduced plasma membrane fluidity: Implications for hypertensive disorders of pregnancy.

Hypertensive disorders of pregnancy (HDPs) affect 5%-10% of pregnant women and, in the absence of established therapies, remain a leading cause of maternal and perinatal mortality. HDPs have been associated with disruption of cytotrophoblast fusion into syncytiotrophoblasts, a process essential for placental development. Here, we identified altered expression of mitochondrial dihydroorotate dehydrogenase (DHODH) and interferon-induced transmembrane proteins (IFITMs), using HDP placentas, and investigated their functional roles in trophoblast fusion and membrane dynamics. In trophoblast cells, the inhibition of DHODH led to upregulated expression of IFITM1-3 through transcription factor IRF1 and suppression of syncytialization. IFITMs also increased the proportion of saturated fatty acids, thereby decreasing plasma membrane fluidity. Furthermore, IFITM2 increased the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt1/PlGF) ratio, a key biomarker of HDP severity. These results suggest that DHODH deficiency activates IRF1-mediated IFITM2 expression, leading to impaired trophoblast fusion via biophysical remodeling of the membrane and contributing to HDP pathogenesis.