Cardiovascular diseases (CVDs), particularly heart failure, are major contributors to early mortality globally. Heart failure poses a significant public health problem, with persistently poor long-term outcomes and an overall unsatisfactory prognosis for patients. Conventionally, treatments for heart failure have focused on lowering blood pressure; however, the development of more potent therapies targeting hemodynamic parameters presents challenges, including tolerability and safety risks, which could potentially restrict their clinical effectiveness. Adenosine has emerged as a key mediator in CVDs, acting as a retaliatory metabolite produced during cellular stress via ATP metabolism, and works as a signaling molecule regulating various physiological processes. Adenosine functions by interacting with different adenosine receptor (AR) subtypes expressed in cardiac cells , including A₁AR, A_2AAR, A_2BAR, and A₃AR. In addition to A₁AR, A₃AR has a multifaceted role in the cardiovascular system, since its activation contributes to reducing the damage to the heart in various pathological states, particularly ischemic heart disease, heart failure, and hypertension, although its role is not as well documented compared to other AR subtypes. Research on A₃AR signaling has focused on identifying the intricate molecular mechanisms involved in CVDs through various pathways, including G_i or G_q protein-dependent signaling, ATP-sensitive potassium channels, MAPKs, and G protein-independent signaling. Several A₃AR-specific agonists, such as piclidenoson and namodenoson, exert cardioprotective impacts during ischemia in the diverse animal models of heart disease. Thus, modulating A₃ARs serves as a potential therapeutic approach, fueling considerable interest in developing compounds that target A₃ARs as potential treatments for heart diseases. Full article