{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:09:25Z","timestamp":1792422565128,"version":"4.5.0"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"37","license":[{"start":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T00:00:00Z","timestamp":1757376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2024B1515020113"],"award-info":[{"award-number":["2024B1515020113"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"crossref","award":["82270500"],"award-info":[{"award-number":["82270500"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"crossref","award":["82203304"],"award-info":[{"award-number":["82203304"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,9,16]]},"abstract":"<jats:p>\n                    Proliferative retinopathy is a leading cause of irreversible blindness in humans; however, the molecular mechanisms behind the immune cell\u2013mediated retinal angiogenesis remain poorly elucidated. Here, using single-cell RNA sequencing in an oxygen-induced retinopathy (OIR) model, we identified an enrichment of sorting nexin (SNX)-related pathways, with SNX3, a member of the SNX family that is involved in endosomal sorting and trafficking, being significantly upregulated in the myeloid cell subpopulations of OIR retinas. Immunostaining showed that SNX3 expression is markedly increased in the retinal microglia\/macrophages of mice with OIR, which is mainly located within and around the neovascular tufts. Myeloid cell-specific deficiency of\n                    <jats:italic toggle=\"yes\">Snx3<\/jats:italic>\n                    inhibited retinal neovascularization, hyperpermeability, and dysfunction in OIR mice. Using glutathione S-transferase pull-down, coimmunoprecipitation, and immunofluorescent staining, we found that SNX3 interacted with receptor-interacting protein 1\/3 (RIP1 and RIP3). We further demonstrated that RIP1\/3 degradation was accelerated in SNX3-deleted microglia\/macrophages, causing an inhibition of hypoxia-induced necroptosis and mitochondrial fission, thereby decreasing the production of proinflammatory and proangiogenic factors (FGF2 and MMP12). Moreover, OIR retinas from myeloid cell\u2013specific SNX3 overexpression transgenic mice presented more angiogenic tufts, while RIP1\/3 inhibition largely ablated SNX3 overexpression\u2013induced pathological angiogenesis. Based on the structure of SNX3, we identified a small-molecule inhibitor, W1122. Intriguingly, we found that W1122 effectively inhibited retinal angiogenesis in the OIR model, and combination treatment with anti-Vascular Endothelial Growth Factor (VEGF) yielded enhanced antiangiogenic effects. Collectively, our findings disclose a link between SNX3 and RIP1\/3 signaling and implicate SNX3 in the development of ischemic retinopathy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2426578122","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T15:36:41Z","timestamp":1757432201000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Sorting nexin 3 promotes ischemic retinopathy through RIP1- and RIP3-mediated myeloid cell necroptosis and mitochondrial fission"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2265-7957","authenticated-orcid":false,"given":"Jiaojiao","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education of China, College of Pharmacy, Jinan University","place":["Guangzhou, China"]},{"name":"Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory of Computer-Aided Drug Design of Dongguan City, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University","place":["Dongguan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhong","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education of China, College of Pharmacy, Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1724-6210","authenticated-orcid":false,"given":"Kai","family":"Zhuang","sequence":"additional","affiliation":[{"name":"School of Public Health, Guangdong Medical University","place":["Dongguan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiami","family":"Zou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education of China, College of Pharmacy, Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanlu","family":"Qiu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education of China, College of Pharmacy, Jinan University","place":["Guangzhou, China"]},{"name":"The Department of Ophthalmology, The First Affiliated Hospital of Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Jin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education of China, College of Pharmacy, Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weile","family":"Ye","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education of China, College of Pharmacy, Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6352-3357","authenticated-orcid":false,"given":"Pinglian","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education of China, College of Pharmacy, Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihua","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education of China, College of Pharmacy, Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Department of Ophthalmology, The First Affiliated Hospital of Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5821-703X","authenticated-orcid":false,"given":"Zunnan","family":"Huang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory of Computer-Aided Drug Design of Dongguan City, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University","place":["Dongguan, 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Yang, J. Zhao, X. Sun, Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: A comprehensive review. Drug Des. Devel. Ther. 10, 1857\u20131867 (2016).","journal-title":"Drug Des. Devel. 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Liu . Single-cell transcriptome analyses reveal microglia types associated with proliferative retinopathy. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE199792. 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