GPR153 is an orphan G protein-coupled receptor of the Rhodopsin (Class A) family with emerging roles in vascular and neurological pathophysiology. Based on phylogenetic modeling, GPR153 likely binds catecholamines (adrenaline and noradrenaline) 1, sharing evolutionary ancestry with GPR162 2. The receptor is widely expressed in the central nervous system, with notably high levels in the thalamus, cerebellum, and arcuate nucleus 2. Mechanistically, GPR153 negatively regulates cellular cAMP levels in both smooth muscle cells (SMCs) and endothelial cells (ECs), thereby suppressing CREB phosphorylation while promoting YAP/TAZ-mediated and NF-κB-driven pro-inflammatory and pro-proliferative gene expression 3. In vascular injury models, GPR153 deficiency reduces SMC proliferation and neointima formation, while EC-specific deletion protects against neuroinflammation and stroke 3. Functionally, GPR153 knockdown alters food intake and affects decision-making behavior 2. Clinically, GPR153 variants have been identified in childhood-onset schizophrenia cases 4, and the receptor is upregulated in various cancers, suggesting potential roles in neuropsychiatric and oncological pathologies 5. Overall, GPR153 represents a promising therapeutic target for vascular remodeling, neuroinflammatory, and psychiatric disorders.