In the present study, we demonstrated for the first time that the inhibition of KCa3.1 channels reduces the induction of AF after prolonged rapid atrial pacing by reducing the polarization of pro-inflammatory macrophages and the secretion of associated inflammatory factors, probably through the p38 MAPK/AP-1/NF-κB signaling pathway. The gene discussed is KCNN4; the disease is atrial fibrillation.