Differential myocardial responses to indobufen and aspirin across clinical and experimental models of myocardial infarction

BACKGROUND: Aspirin remains the cornerstone of antiplatelet therapy for acute myocardial infarction (AMI); however, its use is limited in patients with aspirin intolerance, hypersensitivity, or high bleeding risk. Indobufen, a reversible cyclooxygenase-1 inhibitor, has emerged as a potential alternative, yet its cardioprotective effects beyond platelet inhibition and the underlying mechanisms remain incompletely understood. METHODS: Clinical serum samples were collected from patients with ST-segment elevation myocardial infarction (STEMI) receiving aspirin or indobufen therapy. In parallel, myocardial infarction was induced in mice by left anterior descending coronary artery ligation, and neonatal rat cardiac fibroblasts (NRCFs) were subjected to hypoxia in vitro. Cardiac function, fibrosis, autophagy, apoptosis, and oxidative stress were evaluated using echocardiography, histology, immunostaining, western blotting, and transmission electron microscopy. Publicly available single-cell RNA sequencing data were analyzed to explore relevant cellular pathways. RESULTS: In STEMI patients, indobufen treatment was associated with lower circulating levels of cardiac troponin I, thromboxane B₂, IL-1β, and IL-12, along with increased IL-10 levels than aspirin treatment, and these associations remained significant after multivariable adjustment for baseline clinical characteristics. In vivo, indobufen improved cardiac function and attenuated myocardial fibrosis, accompanied by modulation of autophagy-related signaling, reduced apoptosis, and alleviation of oxidative stress. In vitro, indobufen attenuated hypoxia-induced cardiac fibroblast activation, apoptosis, and mitochondrial dysfunction, whereas aspirin exerted limited effects under the same conditions. Mechanistically, indobufen was associated with increased activation of AKT and AMPK signaling pathways and coordinated modulation of autophagy-related proteins. Further pharmacological inhibition of AMPK partially attenuated the autophagy-related effects of indobufen, suggesting that AMPK signaling contributes, at least in part, to the cytoprotective effects of indobufen. CONCLUSIONS: These findings suggest that indobufen may exert myocardial protective effects beyond platelet inhibition, potentially through AKT/AMPK-associated regulation of autophagy, apoptosis, and fibroblast activation. These findings provide a rationale for further investigation of indobufen as a potential alternative antiplatelet strategy in myocardial infarction.