ADORA2A encodes the adenosine A2a receptor, a G protein-coupled receptor that mediates adenosine signaling through activation of adenylyl cyclase. The receptor plays crucial roles in multiple physiological and pathological processes. In endothelial cells, ADORA2A promotes pathological angiogenesis by enhancing HIF-1α-dependent glycolysis through ERK/Akt signaling pathways 1. The receptor also drives endothelial-to-mesenchymal transition, contributing to subretinal fibrosis in age-related macular degeneration 2. In cancer, ADORA2A upregulation during neuroendocrine differentiation rewires proline metabolism via ERK/MYC/PYCR signaling, promoting epigenetic reprogramming and lineage plasticity 3. The receptor mediates immunosuppressive effects during sepsis, where adenosine produced by CD39hi B cells signals through ADORA2A to impair macrophage function 4. Genetic polymorphisms in ADORA2A influence caffeine metabolism and consumption patterns, with variants affecting habitual caffeine intake by 3-32% 5. Sleep homeostasis involves adenosine signaling, with basal forebrain glutamatergic neurons controlling extracellular adenosine levels 6. These findings highlight ADORA2A as a promising therapeutic target for treating angiogenic diseases, cancer lineage plasticity, and sepsis-induced immunosuppression.