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@ARTICLE{Rehman:866061,
author = {Rehman, Michael and Vodret, Simone and Braga, Luca and
Guarnaccia, Corrado and Celsi, Fulvio and Rossetti, Giulia
and Martinelli, Valentina and Battini, Tiziana and Long,
Carlin and Vukusic, Kristina and Kocijan, Tea and Collesi,
Chiara and Ring, Nadja and Skoko, Natasa and Giacca, Mauro
and Del Sal, Giannino and Confalonieri, Marco and Raspa,
Marcello and Marcello, Alessandro and Myers, Michael P. and
Crovella, Sergio and Carloni, Paolo and Zacchigna, Serena},
title = {{H}igh-throughput screening discovers antifibrotic
properties of haloperidol by hindering myofibroblast
activation},
journal = {JCI insight},
volume = {4},
number = {8},
issn = {2379-3708},
address = {Ann Arbor, Michigan},
publisher = {JCI Insight},
reportid = {FZJ-2019-05301},
pages = {e123987},
year = {2019},
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.},
cin = {IAS-5 / INM-9 / JSC},
ddc = {610},
cid = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121 /
I:(DE-Juel1)JSC-20090406},
pnm = {572 - (Dys-)function and Plasticity (POF3-572) / 511 -
Computational Science and Mathematical Methods (POF3-511)},
pid = {G:(DE-HGF)POF3-572 / G:(DE-HGF)POF3-511},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:30996132},
UT = {WOS:000465334200005},
doi = {10.1172/jci.insight.123987},
url = {https://juser.fz-juelich.de/record/866061},
}