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Despite the critical impact of diabetic retinopathy, the precise mechanism underlying neurovascular coupling and effective strategies to suppress neurovascular dysfunction remain unclear. In this study, the up\u2010regulation of a tRNA\u2010derived stress\u2010induced RNA, 5\u2032tiRNA\u2010His\u2010GTG, in response to diabetic stress is revealed. 5\u2032tiRNA\u2010His\u2010GTG directly regulates M\u00fcller glia action and indirectly alters endothelial angiogenic effects and retinal ganglion cell (RGC) survival in vitro. Downregulation of 5\u2032tiRNA\u2010His\u2010GTG alleviates diabetes\u2010induced retinal neurovascular dysfunction, characterized by reduced retinal vascular dysfunction, decreased retinal neurodegeneration, and improved visually\u2010guided behaviors in vivo. Mechanistically, 5\u2032tiRNA\u2010His\u2010GTG acts as a key regulator of retinal neurovascular dysfunction, primarily by modulating arachidonic acid (AA) metabolism via the CYPs pathway. The 5\u2032tiRNA\u2010His\u2010GTG\u2010CYP2E1\u201019(S)\u2010HETE signaling axis is identified as a key driver of retinal neurovascular dysfunction. Thus, targeting 5\u2032tiRNA\u2010His\u2010GTG presents a promising therapeutic strategy for treating vasculopathy and neuropathy associated with diabetes mellitus. Modulating this novel signaling pathway can open up new avenues for intervention in diabetic retinopathy and its related complications.<\/jats:p>","DOI":"10.1002\/advs.202411042","type":"journal-article","created":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T05:01:21Z","timestamp":1731042081000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Targeting tRNA\u2010Derived Non\u2010Coding RNA Alleviates Diabetes\u2010Induced Visual Impairment through Protecting Retinal Neurovascular Unit"],"prefix":"10.1002","volume":"12","author":[{"given":"Jin","family":"Yao","sequence":"first","affiliation":[{"name":"The Affiliated Eye Hospital Nanjing Medical University  Nanjing 210000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Yao","sequence":"additional","affiliation":[{"name":"The Affiliated Eye Hospital Nanjing Medical University  Nanjing 210000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun\u2010Ya","family":"Zhu","sequence":"additional","affiliation":[{"name":"The Affiliated Eye Hospital Nanjing Medical University  Nanjing 210000 China"},{"name":"School of Medicine Southeast University  Nanjing 210009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"The Affiliated Eye Hospital Nanjing Medical University  Nanjing 210000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin\u2010Hong","family":"Liu","sequence":"additional","affiliation":[{"name":"The Affiliated Eye Hospital Nanjing Medical University  Nanjing 210000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Ke","family":"Ji","sequence":"additional","affiliation":[{"name":"The Affiliated Eye Hospital Nanjing Medical University  Nanjing 210000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi\u2010Shen","family":"Ni","sequence":"additional","affiliation":[{"name":"The Affiliated Eye Hospital Nanjing Medical University  Nanjing 210000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan","family":"Mu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Shanghai General Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 200080 China"},{"name":"Eye Institute and Department of Ophthalmology Eye and ENT Hospital Fudan University  Shanghai 200031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0063-5718","authenticated-orcid":false,"given":"Biao","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Shanghai General Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 200080 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,11,8]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.310221"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2021.04.027"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"S62","DOI":"10.2337\/dc11-S062","volume":"34","year":"2011","journal-title":"A. 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