Firstly, using in vivo and in vitro myocardial I/R models, we demonstrated that PIASy-mediated Cav-3 SUMOylation by SUMO2/3 controlled the magnitude of Cav-3/Nav1.5 interactions, which affected Nav1.5 abundance on cardiomyocyte membranes, subsequently modulating functional cardiac conduction and lethal ventricular arrhythmias. Here, SCN5A is linked to Ventricular arrhythmia.