TY  - JOUR
AU  - Rehman, Michael
AU  - Vodret, Simone
AU  - Braga, Luca
AU  - Guarnaccia, Corrado
AU  - Celsi, Fulvio
AU  - Rossetti, Giulia
AU  - Martinelli, Valentina
AU  - Battini, Tiziana
AU  - Long, Carlin
AU  - Vukusic, Kristina
AU  - Kocijan, Tea
AU  - Collesi, Chiara
AU  - Ring, Nadja
AU  - Skoko, Natasa
AU  - Giacca, Mauro
AU  - Del Sal, Giannino
AU  - Confalonieri, Marco
AU  - Raspa, Marcello
AU  - Marcello, Alessandro
AU  - Myers, Michael P.
AU  - Crovella, Sergio
AU  - Carloni, Paolo
AU  - Zacchigna, Serena
TI  - High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation
JO  - JCI insight
VL  - 4
IS  - 8
SN  - 2379-3708
CY  - Ann Arbor, Michigan
PB  - JCI Insight
M1  - FZJ-2019-05301
SP  - e123987
PY  - 2019
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:30996132
UR  - <Go to ISI:>//WOS:000465334200005
DO  - DOI:10.1172/jci.insight.123987
UR  - https://juser.fz-juelich.de/record/866061
ER  -