Nuclear Receptor ERRγ Protects Against Cardiac Ischemic Injury by Suppressing GBP5‐Mediated Myocardial Inflammation

Myocardial inflammation plays a critical role in the progression of injury following myocardial infarction (MI), yet the transcriptional mechanisms regulating cardiomyocyte inflammation to mitigate post-ischemic injury remain poorly understood. This study elucidated the role of Estrogen-Related Receptor Gamma (ERRγ) in modulating the inflammatory response post-MI, demonstrating that ERRγ expression was downregulated in ischemic tissue and hypoxic neonatal mouse ventricular myocytes (NMVMs). Cardiomyocyte-specific overexpression of ERRγ reduced infarct size, improved cardiac function, and suppressed excessive myocardial inflammation and pyroptosis by binding to the GBP5 promoter, thereby inhibiting GBP5 transcription and reducing NLRP3 inflammasome assembly. The protective effects of ERRγ overexpression were reversed by overexpressing GBP5, and the ERRγ agonist DY131 also improved cardiac function after MI. These findings suggest that ERRγ activation reduces myocardial ischemic injury by regulating cardiomyocyte inflammation and pyroptosis, highlighting ERRγ as a potential novel therapeutic target for attenuating post-MI injury.