Ethyl acetylsalicylate (E-ASA) protects against myocardial ischemia-reperfusion injury.

Timely reperfusion remains the standard therapy for myocardial ischemia, but it inevitably causes myocardial ischemia‑reperfusion injury (IRI), which remains a major clinical challenge. This study aimed to evaluate the cardioprotective effects of aspirin (ASA) and to identify aspirin ester derivatives with improved efficacy and safety profiles. The cardioprotective potential of ASA was validated in established animal models of myocardial IRI. Multiple aspirin ester derivatives were comparatively analyzed and screened based on their structural and physicochemical characteristics. Among these compounds, ethyl acetylsalicylate (E-ASA) was identified as exhibiting higher cell membrane permeability and a lower bleeding risk than ASA. The cardioprotective mechanisms of E-ASA were further investigated using acetylation proteomics and metabolic pathway analysis in myocardial tissue. E-ASA treatment significantly reduced myocardial infarct size and preserved cardiac function following IRI compared with ASA. Proteomic analyses revealed that E-ASA induced hyperacetylation of key metabolic enzymes involved in cardiac energy metabolism, suggesting that its cardioprotective effects may be mediated through modulation of metabolic remodeling. Acute high dose administration of E-ASA also provided stronger cardioprotection than equimolar doses of ASA in both cellular and in vivo models. E-ASA demonstrated improved cardioprotective effects and a lower bleeding tendency compared with aspirin in preclinical models. These findings suggest that E-ASA may represent a potential therapeutic lead requiring further validation for the prevention and treatment of ischemic heart disease.