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Current treatments include intravitreal injections of anti\u2010vascular endothelial growth factor (VEGF) biologics, but these therapeutics are often accompanied by high treatment burden and resistance to therapy. Prior studies indicate that APE1\/Ref\u20101, a multifunctional protein with both endonuclease (APE1) and redox\u2010mediated transcriptional regulatory activity (Ref\u20101), activates multiple pro\u2010angiogenic and pro\u2010inflammatory signaling pathways by chemically reducing key cysteine residues in transcription factors, thereby activating them. Here, we investigated the previously unexplored role of Ref\u20101 in retinal neovascularization. We demonstrate that Ref\u20101 is highly expressed in endothelial cells in human PDR and in the oxygen\u2010induced retinopathy (OIR) mouse model of retinal neovascularization. Ref\u20101 is also highly expressed in microglia and astrocytes in OIR. A small molecule Ref\u20101 redox inhibitor, APX2009, decreased retinal neovascularization in OIR after systemic delivery. In\u00a0vitro, hypoxic endothelial cells did not exhibit upregulation of Ref\u20101 but rather increased Ref\u20101 nuclear localization. APX2009 decreased hypoxic endothelial cell proliferation and HIF\u20101\u03b1 transcriptional activation. Thus, Ref\u20101 redox activity may be a novel therapeutic target for the treatment of retinal neovascularization, making APX2009 a promising systemic therapeutic approach for the treatment of vascular retinopathies such as ROP and PDR.<\/jats:p>","DOI":"10.1096\/fj.202401989rr","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T08:20:01Z","timestamp":1738657201000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Ref\u20101 redox activity regulates retinal neovascularization by modulating transcriptional activation of\n                    <scp>HIF<\/scp>\n                    \u20101\u03b1"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2061-411X","authenticated-orcid":false,"given":"Gabriella D.","family":"Hartman","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Indiana University School of Medicine  Indianapolis 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