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It is induced by a diverse array of etiologies, including recent SARS-CoV-2 infection. The current standard of care for ARDS remains predominantly supportive, underscoring the urgent need for targeted pharmacological interventions. To address this critical gap, we developed an inhibitor of the microtubule accessory factor end-binding protein 3 (EB3), a key mediator of pathological calcium signaling in endothelial cells. During injury, EB3 facilitates inositol 1,4,5-trisphosphate receptor 3 (IP\n                    <jats:sub>3<\/jats:sub>\n                    R3) clustering on the endoplasmic reticulum membrane, activating widespread calcium release from intracellular stores and leading to endothelial barrier disruption. Using nuclear magnetic resonance (NMR)-guided approaches, we designed and optimized a synthetic EB3 inhibitor, termed vascular therapeutics (VT)-109, with enhanced physicochemical properties. We evaluated the therapeutic potential of VT-109 across a wide range of preclinical models in which pathogenic insults target epithelial or endothelial barriers. Treatment with VT-109 promptly restored the tissue\u2012fluid balance in the injured lung by inducing the reannealing of VE-cadherin junctions and restoring the endothelial barrier. In addition to vascular protection, VT-109 improved lung architecture and function, normalized immune responses, and significantly reduced both morbidity and mortality in ARDS models. At the molecular level, VT-109 blocks inflammatory NFAT and NF\n                    <jats:italic>\u03ba<\/jats:italic>\n                    B signaling while concurrently activating FOXM1-dependent endothelial regeneration. These findings support EB3 inhibition as a promising therapeutic strategy for ARDS and highlight VT-109 as a versatile drug candidate capable of addressing the multifaceted pathophysiology of this disease.\n                  <\/jats:p>","DOI":"10.1038\/s41392-025-02461-y","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T04:24:07Z","timestamp":1763439847000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Therapeutic targeting of endothelial calcium signaling accelerates the resolution of lung injury"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0758-0066","authenticated-orcid":false,"given":"Wan Ching","family":"Chan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man Long","family":"Kwok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyan","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazem","family":"Abdelkarim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Le","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deying","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0668-5480","authenticated-orcid":false,"given":"Avik","family":"Banerjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangping","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Class","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlen","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Hailemeskel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raman Ghotra","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1486-8261","authenticated-orcid":false,"given":"Ricardo","family":"Gallardo-Macias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5420-1639","authenticated-orcid":false,"given":"Vadim J.","family":"Gurvich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Maienschein-Cline","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Lindeblad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasim","family":"Kabirov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander V.","family":"Lyubimov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Belvitch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5344-118X","authenticated-orcid":false,"given":"Justin","family":"Richner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadim","family":"Gaponenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulia A.","family":"Komarova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"2461_CR1","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1001\/jama.2016.0291","volume":"315","author":"G Bellani","year":"2016","unstructured":"Bellani, G. et al. 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