Apotent inhibitor ofPAI-1, MDI-2517, mitigates disease severity in a preclinical systemic sclerosis model
Document Type
Article
Publication Date
2026
Department/School
Chemistry
Publication Title
JCI Insight
Abstract
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–associated biological processes. Treatment of SSc dermal fibroblasts with the small-molecule PAI-1 inhibitor MDI-2517 reduced the expression of the profibrotic markers COL1A1 and ACTA2. 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.
Link to Published Version
Recommended Citation
Su, E. J., Tsou, P.-S., Warnock, M., Subbotina, N., Mann, K., Vichaikul, S., Rosek, A., Leung, L., Xing, X., Xing, E., Plazyo, O., Bogle, R., Tsoi, L. C., Emal, C. D., Khanna, D., Varga, J., Sisson, T. H., Gudjonsson, J. E., & Lawrence, D. A. (2026). A potent inhibitor of PAI-1, MDI-2517, mitigates disease severity in a preclinical systemic sclerosis model. JCI Insight, 11(7), e195005. https://doi.org/10.1172/jci.insight.195005
Comments
C. D. Emal is a faculty member in EMU's Department of Chemistry.
See the journal article for a complete list of authors and their affiliations.