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4-Oxo-nonenal (4-ONE) is an endogenous lipid peroxidation product that is more reactive than 4-hydroxy-nonenal (4-HNE). We previously reported the arrhythmic potential of 4-HNE by suppression of cardiac human Ether-a-go-go Related Gene (hERG) K⁺ channels with prolonged action potential duration (APD) in cardiomyocytes. Here, we illustrate the higher arrhythmic risk of 4-ONE by modulating the cardiac hNa_V1.5 channel currents (I_NaV). Although the peak amplitude of I_NaV was not significantly changed by 4-ONE up to 10 μM, the rate of I_NaV inactivation was slowed, and the late Na⁺ current (I_NaL) became larger by 10 μM 4-ONE. The chemical modification of specific residues in hNa_V1.5 by 4-ONE was identified using MS-fingerprinting analysis. In addition to the changes in I_NaV, 4-ONE decreased the delayed rectifier K⁺ channel currents including the hERG current. The L-type Ca²⁺ channel current was decreased, whereas its inactivation was slowed by 4-ONE. The APD prolongation by 10 μM of 4-ONE was more prominent than that by 100 μM of 4-HNE. In the computational in silico cardiomyocyte simulation analysis, the changes of I_NaL by 4-ONE significantly exacerbated the risk of arrhythmia exhibited by the TdP marker, qNet. Our study suggests an arrhythmogenic effect of 4-ONE on cardiac ion channels, especially hNa_V1.5.