ETV1 orchestrates a self-reinforcing ERK1/2-RSK3 signaling loop to drive atrial fibrillation pathogenesis: implications for targeted therapy.

As the most prevalent sustained cardiac arrhythmia, atrial fibrillation (AF) remains incompletely characterized in terms of its molecular drivers. This investigation seeks to systematically identify critical molecular determinants and delineate their regulatory circuitry governing AF pathogenesis. Using integrated transcriptomic and single-cell analyses, we identified ETV1 as a potential AF-associated regulator. Functional validation was performed through gain- and loss-of-function experiments in vitro and in vivo, combined with pharmacological modulation of the ERK1/2-RSK3 pathway and comprehensive cardiac phenotyping. ETV1 was found to be significantly overexpressed in cardiomyocytes from AF patients. Activation of the ERK1/2-RSK3-ETV1 axis induced hallmark AF features, including myocardial fibrosis, electrical remodeling, and calcium dysregulation. Inhibition or genetic ablation of ETV1 reversed these phenotypes and reduced AF susceptibility in vivo. Our findings identify ETV1 as a central regulator of AF pathogenesis, functioning through a self-reinforcing ERK1/2-RSK3-ETV1 signaling loop. Targeting this upstream axis offers a promising therapeutic strategy distinct from conventional downstream modulation approaches.