ADORA3 (adenosine A3 receptor) is a G protein-coupled receptor located on chromosome 1.3 that functions as an inhibitory receptor for adenosine 1. The receptor mediates its effects through G proteins that inhibit adenylyl cyclase activity 2. ADORA3 is widely expressed, with particular abundance in brain and endocrine tissues, as well as the intestinal tract 13. Mechanistically, ADORA3 signaling involves multiple pathways. In microglia, ADORA3 antagonism promotes phagocytosis of myelin debris via the cAMP/PKA/p-CREB pathway 4. In intestinal epithelial cells, ADORA3 activation enhances ketogenesis through HMGCS2, leading to elevated beta-hydroxybutyrate levels that promote goblet cell differentiation via histone acetylation at the ATOH1 promoter 3. Disease relevance spans multiple conditions. ADORA3 elevation is associated with vascular dementia pathogenesis, where antagonism alleviates white matter injury and cognitive impairment 4. Conversely, ADORA3 downregulation in ulcerative colitis impairs mucosal barrier function, suggesting activation could be therapeutic 3. ADORA3 expression is elevated in intracranial aneurysms and correlates with vascular smooth muscle cell autophagy; blood ADORA3 levels show moderate diagnostic value (AUC: 0.756) for IA detection 5. ADORA3 has also been identified as a psychiatric-associated gene in genome-wide association studies of behavioral phenotypes 6.