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A critical early step in this process is the activation of retinal vascular endothelial cells (ECs), which up-regulate adhesion molecules that mediate T cell adhesion and subsequent extravasation. Here, we identify the small terpenoid compound costunolide (COS) as a potent suppressor of retinal endothelial inflammation and disease progression in experimental autoimmune uveitis (EAU). Quantitative proteomics of primary human retinal endothelial cells stimulated with TNF-\u03b1 defined a proinflammatory endothelial signature and revealed induction of adhesion molecules. Screening of a focused library of 337 terpenoids uncovered COS as a top hit that markedly attenuated TNF-\u03b1-induced endothelial activation. In vivo, COS treatment significantly reduced clinical and histopathologic EAU scores, accompanied with reduced endothelial adhesion molecule expression and decreased T cell infiltration. Mechanistically, COS directly targeted deubiquitinase USP15, inhibiting USP15-dependent deubiquitination of TRAF1 and TNF signaling in retinal ECs. These findings establish COS as a candidate therapeutic agent for autoimmune uveitis and reveal a TNF-\u03b1\u2013USP15\u2013TRAF1 axis in retinal endothelium that can be pharmacologically exploited to limit pathogenic leukocyte trafficking.<\/jats:p>","DOI":"10.1073\/pnas.2533845123","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T18:03:18Z","timestamp":1783447398000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Costunolide ameliorates autoimmune uveitis by targeting USP15 to suppress TNF-\u03b1-induced retinal endothelial inflammation"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6863-5967","authenticated-orcid":false,"given":"Yu","family":"Gao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/033vnzz93","id-type":"ROR","asserted-by":"publisher"}],"name":"Ophthalmology Medical Center, The First Affiliated Hospital of 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