Identification of senescence-related genes for potential therapeutic biomarkers of atrial fibrillation by bioinformatics, human histological validation, and molecular docking

Background: Cellular senescence is pivotal in the occurrence and progression of atrial fibrillation (AF). This study aimed to identify senescence-related genes that could be potential therapeutic biomarkers for AF. Methods: AF-related differentially expressed genes (DEGs) were identified using the Gene Expression Omnibus dataset. Weighted gene co-expression network analysis (WGCNA) was used to analyze important modules and potential hub genes. Integrating senescence-related genes, potential biomarkers were identified. Their differential expression levels were then validated in human atrial tissue, HL-1 cells, and Angiotensin II-infused mice. Finally, molecular docking analysis was conducted to predict potential interactions between potential biomarkers and the senolytic drug Navitoclax. Results: We identified seven genes common to AF-related DEGs and senescence-related genes. Three significant modules were selected from WGCNA analysis. Taken together, three senescence-related genes (ETS1, SP1, and WT1) were found to be significantly associated with AF. Protein-protein interaction network analysis revealed biological connections among the predicted target genes of ETS1, SP1, and WT1. Notably, ETS1, SP1, and WT1 exhibited significant differential expression in clinical samples as well as in vitro and in vivo models. Molecular docking revealed favorable binding affinity between senolytic Navitoclax and these potential biomarkers. Conclusions: This study highlights ETS1, SP1, and WT1 as crucial senescence-related genes associated with AF, offering potential therapeutic targets, with supportive evidence of binding affinity with senolytic Navitoclax. These findings provide novel insights into AF pathogenesis from a senescence perspective.