{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:55:43Z","timestamp":1787241343931,"version":"build-2736575974"},"reference-count":87,"publisher":"American Society for Clinical Investigation","issue":"7","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":50,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health, National Heart, Lung, and Blood Institute, and National Institute On Aging, and National Institute Of Arthritis and Musculoskeletal and Skin Diseases.","award":["R01HL055374,R01AG074552,R43AR074318,R44AR074318,R43HL145960,R44HL158435,R01HL163870"],"award-info":[{"award-number":["R01HL055374,R01AG074552,R43AR074318,R44AR074318,R43HL145960,R44HL158435,R01HL163870"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,8]]},"abstract":"<jats:p>\n                    Systemic sclerosis (SSc) is a complex and heterogeneous condition characterized by progressive fibrosis in multiple organs. Recent studies implicate plasminogen activator inhibitor-1 (PAI-1) in the pathogenesis of SSc, and PAI-1 is considered as a potential target for therapy. Here, using single-cell and spatial RNA-seq analysis of skin biopsies from 18 healthy individuals and 22 SSc patients, we found elevated PAI-1 colocalizing to myofibroblasts with enriched extracellular matrix\u2013associated biological processes. Treatment of SSc dermal fibroblasts with the small-molecule PAI-1 inhibitor MDI-2517 reduced the expression of the profibrotic markers\n                    <jats:italic>COL1A1<\/jats:italic>\n                    and\n                    <jats:italic>ACTA2<\/jats:italic>\n                    . To investigate the therapeutic potential of MDI-2517, we evaluated its efficacy in reducing fibrosis in a preclinical model of SSc. Treatment of mice with MDI-2517 significantly reduced both skin and lung fibrosis and was superior to treatment with either pirfenidone or mycophenolate mofetil. Additionally, MDI-2517 attenuated weight loss and significantly reduced the expression of key profibrotic markers. Compared with tiplaxtinin, another PAI-1 inhibitor previously shown to be effective in a model of SSc, MDI-2517 was found to have superior efficacy at a 10-fold lower dose. These findings highlight the role of PAI-1 in the pathogenesis of SSc, and the potential of MDI-2517 for the treatment of SSc.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.195005","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T19:30:23Z","timestamp":1771356623000},"source":"Crossref","is-referenced-by-count":3,"title":["A potent inhibitor of PAI-1, MDI-2517, mitigates disease severity in a preclinical systemic sclerosis model"],"prefix":"10.1172","volume":"11","author":[{"given":"Enming J.","family":"Su","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7149-9115","authenticated-orcid":true,"given":"Pei-Suen","family":"Tsou","sequence":"additional","affiliation":[{"name":"Scleroderma Program, Division of Rheumatology, Department of Internal 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