NPY5R is a G protein-coupled receptor that mediates neuropeptide Y (NPY) and peptide YY signaling through inhibition of adenylate cyclase 1. The receptor plays pleiotropic roles across multiple physiological systems. In metabolic regulation, NPY5R expression in adipose tissue is downregulated by leptin and involved in neuroendocrine control of adipocyte metabolism; reduced NPY5R levels are observed in obesity and insulin resistance 2. NPY5R activation in hepatocytes promotes apolipoprotein A1 synthesis and secretion via ERK1/2 and PKA signaling pathways, suggesting cardioprotective potential through enhanced cholesterol reverse transport 1. Beyond metabolism, NPY5R is essential for extrapulmonary metastasis in Ewing sarcoma through RhoA-dependent cell motility 3, and its inhibition reduces hypoxia-enhanced breast cancer migration and proliferation 4. In normal development, NPY5R is implicated in hippocampal learning and memory; hemizygosity for NPY5R has been associated with autism spectrum disorder in a chromosome 4 deletion case 5. Genetic variation in NPY5R associates with left ventricular hypertrophy phenotypes in hypertensive populations 6. Dysregulated NPY5R expression appears linked to cervical squamous cell carcinoma 7. These findings establish NPY5R as a therapeutic target across obesity, cardiovascular disease, and cancer pathologies.