This title appears in the Scientific Report :
2019
Please use the identifier:
http://hdl.handle.net/2128/23197 in citations.
Please use the identifier: http://dx.doi.org/10.1172/jci.insight.123987 in citations.
High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation
High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation
Fibrosis is a hallmark in the pathogenesis of various diseases, with very limited therapeutic solutions. A key event in the fibrotic process is the expression of contractile proteins, including α-smooth muscle actin (αSMA) by fibroblasts, which become myofibroblasts. Here, we report the results of a...
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Personal Name(s): | Rehman, Michael |
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Vodret, Simone / Braga, Luca / Guarnaccia, Corrado / Celsi, Fulvio / Rossetti, Giulia / Martinelli, Valentina / Battini, Tiziana / Long, Carlin / Vukusic, Kristina / Kocijan, Tea / Collesi, Chiara / Ring, Nadja / Skoko, Natasa / Giacca, Mauro / Del Sal, Giannino / Confalonieri, Marco / Raspa, Marcello / Marcello, Alessandro / Myers, Michael P. / Crovella, Sergio / Carloni, Paolo / Zacchigna, Serena (Corresponding author) | |
Contributing Institute: |
Jülich Supercomputing Center; JSC Computational Biomedicine; INM-9 Computational Biomedicine; IAS-5 |
Published in: | JCI insight, 4 (2019) 8, S. e123987 |
Imprint: |
Ann Arbor, Michigan
JCI Insight
2019
|
PubMed ID: |
30996132 |
DOI: |
10.1172/jci.insight.123987 |
Document Type: |
Journal Article |
Research Program: |
Computational Science and Mathematical Methods (Dys-)function and Plasticity |
Link: |
OpenAccess OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://dx.doi.org/10.1172/jci.insight.123987 in citations.
Fibrosis is a hallmark in the pathogenesis of various diseases, with very limited therapeutic solutions. A key event in the fibrotic process is the expression of contractile proteins, including α-smooth muscle actin (αSMA) by fibroblasts, which become myofibroblasts. Here, we report the results of a high-throughput screening of a library of approved drugs that led to the discovery of haloperidol, a common antipsychotic drug, as a potent inhibitor of myofibroblast activation. We show that haloperidol exerts its antifibrotic effect on primary murine and human fibroblasts by binding to sigma receptor 1, independent from the canonical transforming growth factor-β signaling pathway. Its mechanism of action involves the modulation of intracellular calcium, with moderate induction of endoplasmic reticulum stress response, which in turn abrogates Notch1 signaling and the consequent expression of its targets, including αSMA. Importantly, haloperidol also reduced the fibrotic burden in 3 different animal models of lung, cardiac, and tumor-associated fibrosis, thus supporting the repurposing of this drug for the treatment of fibrotic conditions. |