Histone deacetylases in myocardial infarction: Orchestrating programmed cell death pathways and emerging therapeutic opportunities

Myocardial infarction (MI) remains a major global health challenge, characterized by irreversible cardiomyocyte loss primarily mediated by multiple programmed cell death (PCD) pathways - including apoptosis, necroptosis, autophagy, ferroptosis, and pyroptosis. Histone deacetylases (HDACs) have emerged as pivotal epigenetic regulators orchestrating these diverse PCD processes by modulating the acetylation status of histone and non-histone proteins, thereby significantly influencing myocardial injury, inflammation, oxidative stress, and cardiac remodeling. Individual HDAC isoforms exhibit complex, dual, and context-dependent roles, acting either as promoters or suppressors of cardiomyocyte death depending on cellular stress conditions. This review systematically summarizes recent advances elucidating the isoform-specific roles of HDACs in regulating distinct PCD pathways during MI, highlighting their mechanistic complexity and therapeutic potential. Furthermore, we critically evaluate emerging preclinical strategies targeting HDACs - including inhibitors and activators - and discuss their translational prospects for clinical application. Deciphering isoform-specific HDAC-mediated regulation of cardiomyocyte PCD offers promising avenues to preserve myocardial integrity and improve clinical outcomes following MI.