Purinergic signaling plays a critical role in several inflammatory diseases, including acute lung injury, inflammatory bowel disease, coronary artery diseases, and various cancers. Purine and its derivatives, specifically adenosine and ATP, exhibit a critical regulatory axis that bridges platelet activation, vascular thrombosis, and sterile inflammation. Myocardial infarction (MI) initiates a complex pathophysiological cascade characterized by profound hypoxia, inflammation response, reduced coronary blood flow, and increased oxidative stress, which leads to myocardial cell death and apoptosis. Reperfusion therapy remains a primary strategy for restoring coronary blood flow and maximally limiting infarct size; increased infarct size further exacerbates ischemic injury, making it myocardial ischemic/reperfusion injury (MIRI). In this review, we delineate the mechanistic “triad axis”, comprising adenosine signaling, hypoxia-inducible factor (HIF) stabilization, and reactive oxygen species (ROS) homeostasis; this axis serves as a pivotal determinant of cardiomyocyte death during MIRI. We further examine the cell-specific roles of adenosine signaling in modulating immune cell infiltration and function within the ischemic milieu. Finally, we highlight the emerging role of mitochondrial ROS (mtROS) and HIF-dependent signaling in circadian regulation, suggesting that the chronotherapeutic approaches targeting these pathways may offer transformative opportunities for the treatment of ischemic heart disease (IHD).
Singh et al. (2026) studied this question.