Purinergic Signaling, HIF, and ROS Interactions in Myocardial I/R Injury: Therapeutic Potential and Future...

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).