Abstract
Atrial fibrillation (AF), the most common clinical arrhythmia, is driven by inflammatory activation and oxidative stress, though precise molecular links remain unclear. This study identifies the P2X7 receptor as a key upstream regulator orchestrating proarrhythmic atrial remodeling through reactive oxygen species (ROS)-mediated mitogen-activated protein kinase (MAPK) signaling. Transcriptomic analysis of rapid-paced cardiomyocytes revealed P2X7 upregulation and MAPK pathway enrichment. Functional validation demonstrated that P2X7 activation promotes ROS accumulation, MAPK phosphorylation (p-ERK, p-p38, and p-JNK), and pro-inflammatory cytokine release (IL-6 and IL-1β), culminating in action potential shortening and calcium handling dysfunction. Critically, both P2X7 inhibition (A-438079) and ROS scavenging (NAC) attenuated this signaling axis. In vivo, P2X7 antagonism reduced AF susceptibility, improved conduction heterogeneity, and ameliorated structural and autonomic remodeling. These results establish the P2X7-ROS-MAPK axis as a central mechanism in AF vulnerability and highlight its therapeutic potential.