The Pesticide Pyrethroid Metabolite 3-Phenoxybenzoic Acid (3-PBA) Impairs Human Cardiac Nav1.5 and Action Potential Depolarization

Pyrethroid insecticides (PYRs) are widely used worldwide, and their primary metabolite, 3-phenoxybenzoic acid (3-PBA), serves as a near-ubiquitous biomarker of human exposure to PYRs. While epidemiological data consistently link urinary 3-PBA to increased cardiometabolic risk and coronary heart disease, the underlying electrophysiological mechanisms of its direct potential cardiotoxicity remain unexplored. Parent PYRs are known to exert cardiotoxic effects by enhancing the late sodium current (I Na-L ) and inducing arrhythmia, but the direct effect of 3-PBA on heart excitability has not been previously investigated. This study demonstrates that 3-PBA interacts with human cardiac Na v 1.5 expressed in Human Embryonic Kidney (HEK293) cells, and significantly increases I Na-L in a concentration-dependent manner with an EC 50 of 51.3 ± 5.1 µM. The metabolite does not alter the voltage dependence of activation and inactivation, but it significantly delays the recovery from inactivation of the peak sodium current. In human induced pluripotent stem cell–derived cardiomyocytes (CM-hiPSCs) and adult rat ventricular myocytes, 3-PBA reduced maximal depolarization rate (dV/dt), indicating impaired depolarization dynamics and reduced peak sodium current. At the organ level, acute exposure in isolated rat hearts did not significantly alter standard ECG parameters. Collectively, these findings suggest that 3-PBA is not electrophysiologically inert but directly modulates cardiac sodium channel function, although at supraphysiological concentration. This provides new evidence of the biological activity of 3-PBA and suggests that its cardiotoxic potential may become clinically relevant under conditions of high dose and chronic exposure or in susceptible populations. Graphical Abstract Pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA) increased the late sodium current in Na v 1.5 expressed in Human embryonic kidney 293 and delayed the recovery from inactivation. Also, 3-PBA in relevant concentration to human toxicology reduced the maximal rate of action potential depolarization (dV/dt) in rat ventricular cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocyte. In the ECG of ex vivo heart preparation 3-PBA 1 μM caused non-effect. This provides evidence of the biological activity of 3-PBA and suggests that its cardiotoxic potential may become clinically relevant under conditions of high dose and chronic exposure or in susceptible populations. Created by Servier Medical Art ( https://smart.servier.com ), licensed under CC BY 4.0 ativecommons.org/licenses/by/4.0/). Gemini 3.1 Pro was used to refine the layout and visual presentation of the graphical abstract. The authors reviewed, verified, and approved all generated content.