We demonstrate for the first time that (i) both NDPK-B and SK4 expressions are elevated in ARVC cardiomyocytes; (ii) the application of recombinant NDPK-B into hiPSC-CMs activated SK4 channels enhances both pacemaker activity and arrhythmic events; and (iii) PHP-1 as a phosphohistidine-specific phosphatase acting on SK4 channels suppresses the enhanced pacemaker activity and prevents the occurrence of arrhythmic events in ARVC-hiPSC-CMs. Here, PLPPR4 is linked to arrhythmogenic right ventricular cardiomyopathy.