2025 Volume 45 Issue 1 Pages 5-14
Disease-specific induced pluripotent stem cells（iPSCs）have enabled the reproduction of patient pathologies, elucidation of disease mechanisms, and the development of therapeutic drugs using in vitro human disease models. In this review, we present our findings on the repurposing of FDA-approved drugs for Timothy syndrome（TS）and for, long QT syndrome type 1（LQTS1）and type 2（LQTS2）through the utilization of hiPSCs and mouse models. TS, LQTS1, and LQTS2 are congenital diseases known to cause severe arrhythmia. Disease-specific iPSCs were generated TS（CACNA1C G406R）, LQTS1（KCNQ1 G269S）, and LQTS2（KCNH2 A561V）, and our investigation revealed that the cough suppressor, dextromethorphan（Dxm）, improved QT prolongation. We identified the sigma non-opioid receptor（SIGMAR1）as a novel player involved in these mechanisms. Our research demonstrated that SIGMAR1 is activated by Dxm treatment and acts as a chaperone. It directly interacts with Ca2＋ and K＋ channels, resulting in the restoration of channel function and a shortening of action potential duration in disease-specific iPS cardiomyocytes. Additionally, common mechanisms underlying QT shortening associated with SIGMAR1 were discovered. Furthermore, we established a transgenic mouse model for TS, and Dxm treatment demonstrated therapeutic effects in improving arrhythmias in the TS mouse model. Our study suggests that SIGMAR1 is a potential therapeutic target for TS, LQTS1, and LQTS2. This review provides a detailed explanation of our research and the mechanisms underlying the effects of Dxm treatment.
