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Although recent evidence indicates that reduced retinal capillary density (RCD) may increase DON risk independently of orbital apex crowding, the underlying mechanisms and associated metabolic reprogramming remain unclear. In a retrospective analysis of TAO patients with and without DON, those with DON demonstrated elevated pulse pressure (PP), decreased RCD, and higher incidences of dyslipidemia, hyperglycemia, and internal carotid artery calcification. To explore the metabolic basis of these findings, untargeted and targeted metabolomic profiling of plasma from TAO patients and healthy controls was conducted, identifying DON\u2010associated abnormalities in the L\u2010arginine metabolic pathway (registration number: ChiCTR2000035598). Integrating these results with existing literature suggests that oxidative stress drives dysregulated L\u2010arginine\u2013nitric oxide (NO) metabolism, contributing to progressive RCD loss. In early\u2010stage DON patients treated with oral L\u2010arginine, improvements in RCD, PP, and visual function were observed (registration number: ChiCTR2300076962). Further analyses implicated reduced NO bioavailability, due to L\u2010arginine depletion and endothelial NO synthase (eNOS) uncoupling, as a key contributor to declining RCD. Given that oral L\u2010arginine can improve PP via NO\u2010mediated pathways in cardiovascular disease, our findings offer a promising new therapeutic direction for DON management.<\/jats:p>","DOI":"10.1002\/mco2.70652","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T11:12:44Z","timestamp":1772968364000},"source":"Crossref","is-referenced-by-count":1,"title":["Retinal Capillary Density Reduction Contributes to Dysthyroid Optic Neuropathy via an\u00a0L\u2010Arginine\u2010NO Pathway: A Metabonomics and Clinical Trial Study"],"prefix":"10.1002","volume":"7","author":[{"given":"Yunhai","family":"Tu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Ophthalmology Optometry and Visual Science Eye Hospital Wenzhou Medical University  Wenzhou China"},{"name":"National Clinical Research Center for Ocular Diseases Eye Hospital Wenzhou Medical University  Wenzhou 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