Radiation-induced heart disease is a well-recognized complication of thoracic radiotherapy, with atrial fibrillation (AF) being a particularly notable sequela. The mechanisms by which ionizing radiation (IR) heightens susceptibility to AF remain inadequately understood. This study seeks to elucidate the role of cellular senescence and the GATA4-NF-κB signaling pathway in radiation-induced atrial remodeling and the pathogenesis of AF. An in vivo mouse model was developed through localized cardiac irradiation using 20 Gy X-rays. The irradiated mice demonstrated dose-dependent atrial structural and electrophysiological remodeling. Transcriptomic analysis revealed significant enrichment in DNA damage response (DDR), NF-κB signaling, and aging-related pathways. IR exposure induced substantial DNA damage, activated ATM/ATR pathways, and enhanced autophagic flux. These responses culminated in the accumulation of GATA4 and phosphorylation of NF-κB, which drove the expression of the senescence-associated secretory phenotype (SASP), coinciding with increased senescence-associated β-galactosidase (SA-β-gal) activity. In vitro, these crucial findings were recapitulated using irradiated HL-1 atrial cardiomyocytes, whereas the knockdown of GATA4 effectively suppressed both cellular senescence and SASP expression. Notably, treatment with the senolytic combination of dasatinib and quercetin (D/Q) alleviated DNA damage, inhibited excessive autophagy, and suppressed the GATA4-NF-κB pathway in irradiated mice, thereby reducing SASP levels. These improvements resulted in the reversal of atrial structural and electrophysiological remodeling and a marked reduced susceptibility to AF. Overall, our findings demonstrate that IR promotes atrial remodeling by inducing DNA damage-mediated cellular senescence via the GATA4-NF-κB-SASP axis. Targeting this pathway with senolytics such as D/Q thus identifies a promising therapeutic strategy for preventing radiation-induced atrial fibrillation.
