{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:11:49Z","timestamp":1788876709568,"version":"build-2803163510"},"reference-count":154,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Extracellular purinergic signaling, mediated by nucleotides such as adenosine triphosphate (ATP) and adenosine, is a critical regulator of retinal homeostasis. Within the retina, this signaling pathway is indispensable for maintaining physiological functions. Dysregulation of extracellular purine balance is a key driver of retinal pathophysiology, contributing to inflammation, pathological angiogenesis, and neurodegeneration in diseases like diabetic retinopathy (DR), age-related macular degeneration (AMD), glaucoma, and retinopathy of prematurity (ROP). The hydrolysis of extracellular ATP to adenosine, primarily orchestrated by the sequential actions of NTPDase1\/ENTPD1 (CD39) and ecto-5\u2032-nucleotidase\/NT5E (CD73), represents a fundamental mechanism for calibrating purinergic signals and shifting the microenvironment from pro-inflammatory to anti-inflammatory and protective. CD39 and CD73 are pivotal enzymes in regulating retinal purinergic equilibrium. Despite their well-characterized roles in tumor biology and cerebral pathophysiology, the expression, physiological functions, and pathological implications of CD39\/CD73 in the retina remain understudied and lack systematic synthesis. This review synthesizes current understanding of the roles of CD39 and CD73 in retinal physiology and pathology, with a focus on their implications in DR, AMD, glaucoma, and ROP. Critically, this review provides the first systematic integration of their layer-specific spatial compartmentalization, context-dependent functional duality, and emerging metabolic roles in photoreceptor homeostasis. We also discuss emerging therapeutic strategies that target this pathway, addressing the growing need for translational research to preserve vision.<\/jats:p>","DOI":"10.3389\/fcell.2026.1893953","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:57:21Z","timestamp":1788875841000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The CD39-CD73-adenosine axis: a pivotal regulator of retinal homeostasis and diseases"],"prefix":"10.3389","volume":"14","author":[{"given":"Xinyi","family":"Chen","sequence":"first","affiliation":[{"name":"West China School of Medicine, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Department of Optometry and Visual Science, Laboratory of Optometry and Vision Sciences, West China Hospital, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Department of Optometry and Visual Science, Laboratory of Optometry and Vision Sciences, West China Hospital, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Department of Optometry and Visual Science, Laboratory of Optometry and Vision Sciences, West China Hospital, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Department of Optometry and Visual Science, Laboratory of Optometry and Vision Sciences, West China Hospital, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longqian","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Department of Optometry and Visual Science, Laboratory of Optometry and Vision Sciences, West China Hospital, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyi","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Department of Optometry and Visual Science, Laboratory of Optometry and Vision Sciences, West China Hospital, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"261","DOI":"10.2337\/dbi16-0047","article-title":"M\u00fcller cell-microglia cross talk drives neuroinflammation in diabetic retinopathy","volume":"66","author":"Abcouwer","year":"2017","journal-title":"Diabetes"},{"key":"B2","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1007\/s12015-019-09918-y","article-title":"The inhibition of CD39 and CD73 cell surface ectonucleotidases by small molecular inhibitors enhances the mobilization of bone marrow residing stem cells by decreasing the extracellular level of adenosine","volume":"15","author":"Adamiak","year":"2019","journal-title":"Stem Cell Rev. 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