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.

High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation

Braga, Luca;Celsi, Fulvio;Martinelli, Valentina;Collesi, Chiara;Giacca, Mauro;Del Sal, Giannino;Confalonieri, Marco;Marcello, Alessandro;Crovella, Sergio;Zacchigna, Serena
2019-01-01

Abstract

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.
2019
18-apr-2019
Pubblicato
https://insight.jci.org/articles/view/123987
File in questo prodotto:
File Dimensione Formato  
Rehman et al., 2019.pdf

Accesso chiuso

Descrizione: Articolo principale
Tipologia: Documento in Versione Editoriale
Licenza: Copyright Editore
Dimensione 3.64 MB
Formato Adobe PDF
3.64 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
jci.insight.123987.sd.pdf

Accesso chiuso

Descrizione: Supplementary data
Tipologia: Altro materiale allegato
Licenza: Copyright Editore
Dimensione 4.65 MB
Formato Adobe PDF
4.65 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2944008
Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 15
  • ???jsp.display-item.citation.isi??? 15
social impact