Dihydroorotate dehydrogenase (DHODH) regulates trophoblast syncytialization through organelle stress-induced cellular senescence.

Trophoblast syncytialization is essential for placental function, and its dysregulation contributes to hypertensive disorders of pregnancy (HDPs), which compromise maternal and fetal health. Reduced expression of mitochondrial dihydroorotate dehydrogenase (DHODH) was observed in early-onset HDP placentas in our previous study. Experiments using human trophoblast stem cells demonstrated that DHODH inhibition impairs syncytialization and induces cellular senescence via mitochondrial and endoplasmic reticulum stress, elevating sFlt1/PlGF levels, a hallmark of placental dysfunction in HDPs. Mitochondrial activators quercetin and riboflavin partially reversed these effects. Our findings suggest that DHODH may be a key regulator of trophoblast differentiation by linking organelle stress to cellular senescence.