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000866061 1001_ $$0P:(DE-HGF)0$$aRehman, Michael$$b0
000866061 245__ $$aHigh-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation
000866061 260__ $$aAnn Arbor, Michigan$$bJCI Insight$$c2019
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000866061 520__ $$aFibrosis 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.
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000866061 7001_ $$0P:(DE-HGF)0$$aVodret, Simone$$b1
000866061 7001_ $$0P:(DE-HGF)0$$aBraga, Luca$$b2
000866061 7001_ $$00000-0001-7013-0861$$aGuarnaccia, Corrado$$b3
000866061 7001_ $$00000-0002-9760-8463$$aCelsi, Fulvio$$b4
000866061 7001_ $$0P:(DE-Juel1)145921$$aRossetti, Giulia$$b5
000866061 7001_ $$0P:(DE-HGF)0$$aMartinelli, Valentina$$b6
000866061 7001_ $$0P:(DE-HGF)0$$aBattini, Tiziana$$b7
000866061 7001_ $$0P:(DE-HGF)0$$aLong, Carlin$$b8
000866061 7001_ $$0P:(DE-HGF)0$$aVukusic, Kristina$$b9
000866061 7001_ $$00000-0003-0486-7747$$aKocijan, Tea$$b10
000866061 7001_ $$00000-0003-3909-422X$$aCollesi, Chiara$$b11
000866061 7001_ $$0P:(DE-HGF)0$$aRing, Nadja$$b12
000866061 7001_ $$0P:(DE-HGF)0$$aSkoko, Natasa$$b13
000866061 7001_ $$0P:(DE-HGF)0$$aGiacca, Mauro$$b14
000866061 7001_ $$0P:(DE-HGF)0$$aDel Sal, Giannino$$b15
000866061 7001_ $$00000-0002-4791-768X$$aConfalonieri, Marco$$b16
000866061 7001_ $$00000-0002-3437-2430$$aRaspa, Marcello$$b17
000866061 7001_ $$0P:(DE-HGF)0$$aMarcello, Alessandro$$b18
000866061 7001_ $$0P:(DE-HGF)0$$aMyers, Michael P.$$b19
000866061 7001_ $$00000-0001-8493-1168$$aCrovella, Sergio$$b20
000866061 7001_ $$0P:(DE-Juel1)145614$$aCarloni, Paolo$$b21
000866061 7001_ $$00000-0001-6705-3076$$aZacchigna, Serena$$b22$$eCorresponding author
000866061 773__ $$0PERI:(DE-600)2874757-4$$a10.1172/jci.insight.123987$$gVol. 4, no. 8, p. e123987$$n8$$pe123987$$tJCI insight$$v4$$x2379-3708$$y2019
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