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Through comprehensive plasma metabolomics analysis performed in both TAD patients and a \u03b2\u2010aminopropionitrile monofumarate (BAPN)\u2010induced mouse model, significant elevation of 12\u2010hydroxyeicosatetraenoic acid (12\u2010HETE) was identified, accompanied by marked upregulation of its synthetic enzyme 12\/15\u2010lipoxygenase (12\/15\u2010LOX) in dissected aortic tissues. The pathogenetic significance was further demonstrated by the substantial protection against TAD progression that was observed in Alox15\u2010deficient mice. Mechanistically, 12\u2010HETE was confirmed to function as an endogenous ligand for the BLT2 receptor on macrophages, leading to activation of the NOX\u20101\/ROS\/NF\u2010\u03baB signaling cascade. This signaling activation was shown to induce inflammatory cytokine release and promote inflammatory cell recruitment, ultimately resulting in pathological phenotype switching of vascular smooth muscle cells. The therapeutic potential was validated by significant reduction in dissection rupture rates that was achieved with either the 12\/15\u2010LOX inhibitor ML351 or the BLT2 antagonist LY255283, with maximal efficacy being demonstrated when both agents were administered in combination. These findings establish the 12\u2010HETE\u2010BLT2 axis as a key driver of TAD pathogenesis and validate its potential as a promising therapeutic target for clinical intervention.<\/jats:p>","DOI":"10.1002\/advs.202515897","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T05:36:57Z","timestamp":1762407417000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["12\u2010HETE is an Endogenous Modulator of BLT2 Triggering Vascular Degeneration, Dissection, and Rupture"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3984-0889","authenticated-orcid":false,"given":"Yuyu","family":"Li","sequence":"first","affiliation":[{"name":"Beijing Anzhen Hospital Capital Medical University Key Laboratory of Remodeling\u2010related Cardiovascular Diseases Ministry of Education Beijing Collaborative Innovation Centre for Cardiovascular Disorders  No. 2 Anzhen Road, 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