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However, no treatments currently exist that therapeutically target this integrin. We previously identified inducible co-stimulator ligand (ICOSL) as an endogenous antagonist of \u03b1v\u03b23 integrin that protects kidney function through its arginine-glycine-aspartic acid (RGD) motif, independent of its canonical role in immunity. Leveraging the therapeutic advantages of small peptides and the renoprotective function of ICOSL, we used a structure-guided approach to design a 19-amino acid human ICOSL-derived peptide (hICOSL-19) containing the RGD motif and evaluated its therapeutic potential for proteinuric kidney disease. hICOSL-19 exhibited high-affinity binding to \u03b1v\u03b23 integrin, similar to full-length ICOSL, and retained its \u03b1v\u03b23-antagonistic activity. PEGylation of hICOSL-19 (PhICOSL-19) extended its circulating half-life while preserving its antagonistic function. In murine models of acute and chronic proteinuric kidney disease, including immune-mediated glomerulonephritis and diabetic nephropathy, PhICOSL-19 treatment significantly reduced proteinuria, limited glomerular injury, and preserved podocyte architecture. In vitro and in vivo safety assessments further showed no detectable podocyte cytotoxicity, T-cell activation, or anti-drug antibody response. These findings suggest that an ICOSL-derived peptide targeting \u03b1v\u03b23 integrin represents a potential therapeutic strategy for proteinuric kidney diseases associated with \u03b1v\u03b23 integrin activation.<\/jats:p>","DOI":"10.1186\/s43556-026-00594-2","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:20:02Z","timestamp":1791516002000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An inducible co-stimulator ligand (ICOSL)-based peptide therapy for proteinuric kidney diseases targeting \u03b1v\u03b23 integrin"],"prefix":"10.1186","volume":"7","author":[{"given":"Alexis P.","family":"Jimenez-Uribe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxia","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Spear","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwi Hye","family":"Koh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian P.","family":"Mansini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariana G.","family":"Alcantar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Kliewe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Endlich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Reiser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Mangos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0343-7473","authenticated-orcid":false,"given":"Eunsil","family":"Hahm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"issue":"4","key":"594_CR1","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1681\/ASN.2021101319","volume":"33","author":"M Rogg","year":"2022","unstructured":"Rogg M, Maier JI, Van Wymersch C, Helmstadter M, Sammarco A, Lindenmeyer M, et al. alpha-Parvin defines a specific integrin adhesome to maintain the glomerular filtration barrier. 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