ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Signaling
Coq4 deficiency induces placental vascular development defects through FSP1/CoQ10 axis-mediated endothelial ferroptosis
Rui Chen 1
Sikun Wang 1
Xueke He 2
Zhanbiao Wang 1
Miao Jiang 1
1. University of South China, Hengyang, China
2. Southwest University, Chongqing, China
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Abstract
Coenzyme Q10 (CoQ10), a critical electron carrier in mitochondrial respiratory chains, is essential for cellular energy metabolism. Ubiquinone biosynthesis protein 4 homolog (Coq4), a rate-limiting enzyme in CoQ10 biosynthesis, is indispensable for embryonic development. However, the mechanisms underlying Coq4 deficiency-induced developmental defects remain elusive. Emerging evidence highlights the FSP1/CoQ10 axis as a central regulator of lipid peroxidation and ferroptosis, a non-apoptotic cell death mechanism implicated in placental vascular dysgenesis and trophoblast dysfunction. This study aims to elucidate the molecular mechanisms by which Coq4 deficiency disrupts placental development, with a focus on the interplay between the FSP1/CoQ10 axis and endothelial ferroptosis. Coq4+/− mice were generated via CRISPR-Cas9-mediated genome editing. Offspring were genotyped by Polymerase Chain Reaction (PCR), and placental tissues were collected at E9.5 for histological analysis and immunofluorescence. Lentivirus-mediated Coq4 knockdown in human umbilical vein endothelial cells (HUVECs) was combined with RNA sequencing (RNA-seq) to identify differentially expressed genes. Key pathway proteins were validated by Western blotting. Coq4−/− embryos exhibited embryonic lethality and the placentas showed vascular rarefaction and impaired trophoblast invasion. Transcriptomic profiling and Western blotting identified upregulated ferroptosis-related genes including acyl-CoA synthase long-chain family member 4 (ACSL4), ferritin heavy chain 1(FTH1) and downregulated Ferroptosis Suppressor Protein 1(FSP1), but without changes observed on the glutathione peroxidase 4 (GPX4). FSP1 overexpression or CoQ10 supplementation alone partially alleviates ferroptosis whereas combined intervention more effectively improves it. This study demonstrates that Coq4 deficiency induces endothelial ferroptosis via disrupting the FSP1-CoQ10 antioxidant axis, and may also provide new insights into the pathogenesis of pregnancy complications caused by placental dysfunction and iron-related vascular diseases, while offering novel approaches for exploring potential therapeutic targets.
Summary
Keywords
CoQ10, CoQ4, ferroptosis, FSP1, Placental development
Received
23 December 2025
Accepted
20 February 2026
Copyright
© 2026 Chen, Wang, He, Wang and Jiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Miao Jiang
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