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

FEBS Open Bio 2026 Open access

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Authors: Kanoko Yoshida, Kazuya Kusama, Ayaka Horiuchi, Yu Kawaguchi, Atsuya Tsuru, Mikihiro Yoshie, Kazuhiro Tamura
DOI: 10.1002/2211-5463.70194
Cited by: 1
References: 23

Abstract

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.

Fields of Study & Subjects

Pregnancy and preeclampsia studies Neonatal Health and Biochemistry Birth Development and Health

Publication details

Journal / source
FEBS Open Bio
Publisher
Wiley
Volume
16
Issue
6
Pages
1166–1180
Publication date
16 January 2026
Language
EN