Application of hiPSC-CMs model to compare the reversal effects and mechanisms of different drugs on thioridazine-induced acLQTS

Drug targeting of the human ether-à-go-go-related gene (hERG)-encoded rapid delayed rectifier potassium channel induces acquired long QT syndrome (acLQTS), predisposing individuals to life-threatening arrhythmias. Previous studies demonstrate that the antipsychotic agent thioridazine (THIO) triggers acLQTS. Our findings aimed to elucidate the underlying mechanisms of the therapeutic effects against drug-induced cardiotoxicity. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) integrated with multi-electrode arrays (MEA) and optical mapping technology, we evaluated and compared the efficacy of tanshinone IIA (TANIIA), propranolol (Prop) and resveratrol (Res) in reversing THIO-induced prolongation of action potential duration (APD) and field potential duration (all animal experiments were conducted in accordance with the Animal Care Guidelines of Harbin Medical University and were approved by the Ethics Committee of Harbin Medical University, the approval number is IRB3020622). The results showed that TANIIA significantly reversed the THIO-induced prolongation of APD₉₀, APD₅₀, and field potential, whereas neither Prop nor Res counteracted this effect. Building on these results, we further explored the mechanistic basis and molecular targets underlying TANIIA's reversal effects. Western blot and whole-cell patch-clamp demonstrated that TANIIA restored hERG protein expression downregulated by THIO and rescued its channel trafficking defects and rescued channel trafficking defects. Mechanistically, TANIIA attenuated THIO-induced aberrant interactions between hERG and the calnexin, thereby rectifying impaired channel folding and trafficking. Concurrently, TANIIA substantially reduced THIO-induced L-type calcium current. In conclusion, TANIIA ameliorates THIO-induced acLQTS by up regulating hERG current expression and down regulating L-type calcium current. These findings highlight its therapeutic potential of drug-induced acLQTS for clinical.