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Yet, its role in vascular pathophysiology remains poorly defined. This study demonstrates that NARFL deficiency triggers ferroptosis, leading to severe vascular endothelial dysfunction across species. In zebrafish, narfl knockout causes embryonic lethality, accompanied by neurovascular defects, blood\u2010brain barrier disruption, and aberrant hemodynamics. Similarly, knockout of the murine ortholog (Ciao3) results in mid\u2010gestational embryonic lethality due to impaired vascular development and endothelial progenitor cell maturation. Mechanistically, NARFL deficiency disrupts CIA complex assembly, compromising Fe\u2010S cluster transfer to client apo\u2010proteins and leading to a functional shift of cytosolic aconitase (ACO) to iron regulatory protein 1 (IRP1), causing iron overload, heightened oxidative stress, and lipid peroxidation. Consequently, key anti\u2010ferroptotic defenses are suppressed, culminating in endothelial ferroptosis. This pathway is conserved in human endothelial cells, where NARFL deficiency recapitulates the ferroptotic phenotype and functional impairments, which are rescued by the ferroptosis inhibitor. Clinically, specific NARFL polymorphisms have been identified as conferring susceptibility to vascular endothelial disorders (pulmonary hypertension, epilepsy, and neurodegenerative diseases). The work unveils a novel CIA\u2010ferroptosis\u2010vascular axis, positioning NARFL as a critical guardian of endothelial health and a potential therapeutic target.<\/jats:p>","DOI":"10.1002\/advs.202415580","type":"journal-article","created":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T16:55:33Z","timestamp":1764521733000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NARFL Knockout Triggers Ferroptosis\u2010Driven Vascular Endothelial Dysfunction"],"prefix":"10.1002","volume":"13","author":[{"given":"Hui","family":"Hu","sequence":"first","affiliation":[{"name":"Center for Gene Diagnosis and Department of Clinical Laboratory Medicine Zhongnan Hospital of Wuhan University  Wuhan Hubei 430071 China"},{"name":"Department of Laboratory Medicine Shanghai East Hospital Tongji University School of Medicine  Shanghai 200123 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