Integrated multi-omics analysis identifies a senescence-associated myeloid transcriptional program in acute myocardial infarction

Acute myocardial infarction (AMI) triggers extensive immune activation that critically contributes to cardiac injury and post-infarction remodeling. Although senescence-associated molecular programs have been increasingly implicated in cardiovascular disease, their cellular distribution and systemic immune relevance in AMI remain incompletely understood. Herein, we use multi-omics analyses to identify a myeloid-centered senescence-associated program in AMI. Senescence-associated transcriptional activity was predominantly enriched in myeloid cells, with myeloid populations showing higher senescence-associated transcriptional scores exhibiting inflammatory and secretory features. Senescence-associated transcriptional activity was spatially associated with myeloid-enriched regions within the infarcted myocardium during the early post-MI phase. Sensitivity analyses indicated that the cell-cycle-arrest/DDR-associated component was not fully explained by inflammatory/SASP activity. Integrative analyses across cardiac tissue and peripheral blood datasets identified a reproducible senescence-associated gene signature across cardiac and peripheral blood datasets. Among the identified genes, AQP9 and SOCS3 showed robust discriminative performance across independent cohorts, with consistent performance across multiple classification algorithms. Immune cell infiltration analysis and single-cell analyses linked both genes to myeloid-enriched inflammatory states, while gene set enrichment analyses associated their expression with innate immune activation and repression of cell cycle related pathways. Validation using coronary blood samples in our in-house cohort further supported elevated expression of AQP9, SOCS3, and the cell-cycle arrest-associated gene CDKN1A in patients with AMI. Collectively, our findings identify a conserved myeloid-centered senescence-associated inflammatory program in AMI and highlight coordinated changes between tissue-level immune remodeling and systemic transcriptional alterations. These findings provide insight into senescence-associated immune remodeling in AMI and highlight AQP9 and SOCS3 as candidate genes linked to this myeloid inflammatory activation.