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 T1 - High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation PY - 2019/04/18/ 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.123987 VL - 4 IS - 8 UR - https://doi.org/10.1172/jci.insight.123987 PB - The American Society for Clinical Investigation ER -