Therapeutic potential of ADAR1-regulated macrophage exosomes for improving myocardial damage in septic cardiomyopathy

BACKGROUND: Sepsis-induced cardiomyopathy (SICM) is a critical cardiovascular complication characterized by cardiac dysfunction and high mortality. The molecular mechanisms that underlie SICM remain elusive, and effective therapies are limited. RESULTS: Here, we report a pivotal role for adenosine deaminases acting on RNA-1 (ADAR1) in modulating macrophage polarization and exosome-mediated intercellular communication, which ameliorates myocardial damage in SICM. We determined that ADAR1 overexpression in macrophages promotes an anti-inflammatory M2 phenotype, reduces myocardial inflammation, and inhibits cardiomyocyte apoptosis in a murine model of sepsis. Mechanistically, ADAR1 regulates the level of microRNA-122 (miR-122) in macrophage-derived exosomes. Exosomal miR-122 targets X-linked inhibitor of apoptosis protein (XIAP), modulating cardiomyocyte survival. CONCLUSIONS: Our study reveals a novel ADAR1-miR-122-XIAP axis in macrophage exosomes that protects against sepsis-induced myocardial injury, offering a potential disease modulation strategy for SICM.