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Impaired angiogenesis and compromised vascular integrity are fundamental features of diabetic vascular complications to pathophysiological conditions. Emerging evidence highlights the SLIT\/ROBO signaling pathway, which was first identified for its function in axonal guidance and is now recognized as a crucial regulator of angiogenesis and vascular development. In this review, the dualistic role of SLIT\/ROBO signaling is discussed with particular emphasis on its context\u2010dependent regulation of angiogenesis, vascular endothelial permeability, and vascular homeostasis. The classical signaling cascade involving SRGAPs\/Rho GTPases, as well as its non\u2010classical crosstalk with VEGF, PI3K\/Akt, and TGF\u2010\u03b21, illustrate its potential for the regulation of these vascular processes. Evidence from the retina, kidney, brain, and skin will highlight the tissue\u2010specific expression dynamics of SLITs and ROBOs, particularly in the context of hyperglycemic stress. This review discusses the dual role of its member, ROBO4, which has the potential to act as a protective or pathologic factor depending on the vascular microenvironment. In addition, the epigenetic regulation of SLIT2\/ROBO signaling through microRNAs, including miR\u201015a, miR\u2010125b\u20105p, miR\u2010146a\u20105p, and miR\u2010411, provide\u00a0a new perspective, especially with respect to diabetic retinopathy. A deeper understanding of the intricacies\u00a0of the SLIT\/ROBO signaling axis paves\u00a0the way for further research into SLIT2 mimetics, agonists of its member, ROBO4, as well as microRNA\u2010based therapeutic targets.<\/jats:p>","DOI":"10.1002\/cph4.70210","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T13:01:23Z","timestamp":1783083683000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>SLIT<\/scp>\n                    \u2013\n                    <scp>ROBO<\/scp>\n                    Signaling in Diabetes: A Dual Regulator of Angiogenesis and Vascular Dysfunction"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6912-6754","authenticated-orcid":false,"given":"Ravichandran","family":"Sanjai","sequence":"first","affiliation":[{"name":"Department of Biotechnology, School of Bioengineering SRM Institute of Science and Technology  Kattankulathur Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devaprakash","family":"Nithya","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, School of Bioengineering SRM Institute of Science and Technology  Kattankulathur Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5450-902X","authenticated-orcid":false,"given":"Kunka Mohanram","family":"Ramkumar","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, School of Bioengineering SRM Institute of Science and Technology  Kattankulathur Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-017-4214-6"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.13289"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc14-S081"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9103289"},{"issue":"2","key":"e_1_2_12_6_1","first-page":"57","article-title":"Brief Update on Diabetes for General Practitioners","volume":"19","author":"Barquilla Garcia A.","year":"2017","journal-title":"Revista Espa\u00f1ola de Sanidad Penitenciaria"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom13050785"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17651-1"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-28151-9_9"},{"issue":"10","key":"e_1_2_12_10_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0185795","article-title":"The Expression of the Slit\u2010Robo Signal in the Retina of Diabetic Rats and the Vitreous or Fibrovascular Retinal Membranes of Patients With Proliferative Diabetic Retinopathy","volume":"12","author":"Boulton M. 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