Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current

Voltage-gated sodium channels (Na_v channels) support the genesis and brisk spatial propagation of action potentials in the heart. Disruption of Na_V1.5 inactivation results in a small persistent sodium influx known as late sodium current (I _Na,L), which has emerged as a common pathogenic mechanism in both congenital and acquired cardiac arrhythmogenic syndromes. In the present study, using low-noise multichannel recordings in heterologous systems, LQTS3 patient-derived induced pluripotent stem cell cardiomyocytes and mouse ventricular myocytes, we demonstrate that the intracellular fibroblast growth factor homologous factors (FHF1–4) tune pathogenic I _Na,L in an isoform-specific manner. This scheme suggests a complex orchestration of I _Na,L in cardiomyocytes that may contribute to variable disease expressivity of Na_V1.5 channelopathies. We further leverage these observations to engineer a peptide inhibitor of I _Na,L with a higher efficacy compared with a well-established small-molecule inhibitor. Overall, these findings lend insights into molecular mechanisms underlying FHF regulation of I _Na,L in pathophysiology and outline potential therapeutic avenues.