DECR1 deficiency activates a lipid peroxidation-mitocytosis-mitochondrial dysfunction axis in trophoblasts to promote preeclampsia.

Abstract

Preeclampsia (PE) is a pregnancy disorder characterized by placental maladaptation and maternal hypertension, with oxidative stress and lipid peroxidation as central features. Here we identify 2,4-dienoyl-CoA reductase 1 (DECR1), the rate-limiting enzyme in the auxiliary β-oxidation of unsaturated fatty acids, as a key regulator of trophoblast lipid redox balance. DECR1 expression is reduced in placentas from patients with late-onset preeclampsia (LOPE) and an L-NAME-induced PE mouse models. Genetic or pharmacological inhibition of DECR1 increases PUFA-rich lipid accumulation, enhances lipid peroxidation, and induces mitochondrial dysfunction, leading to loss of membrane potential, reactive oxygen species buildup, ATP depletion, and impaired trophoblast migration and invasion. In vivo, DECR1 inhibition causes hypertension, renal injury, fetal growth restriction, and defective placental vascular remodeling. Mechanistically, DECR1 loss disrupts mitochondrial quality control by suppressing mitocytosis, effects that are reversed by radical-trapping agents or mitochondria-targeted antioxidants. Liproxstatin-1 treatment restores maternal, fetal, and placental homeostasis. These findings define a DECR1-lipid peroxidation-mitochondria axis that maintains trophoblast function and placental adaptation, highlighting DECR1 as a potential therapeutic target for PE.