NPFFR2 (neuropeptide FF receptor 2) is a G protein-coupled receptor that primarily binds neuropeptide FF (NPFF) and related RFamide peptides, mediating diverse physiological functions through Gi/o protein coupling and inhibition of cAMP production 1 2 3. The receptor shows selective recognition of NPFF over other RFamide peptides through conserved C-terminal RF-amide interactions in the orthosteric pocket and N-terminal variations that drive subtype specificity 3 4. NPFFR2 plays significant roles in blood pressure regulation through renal autocrine signaling, where it decreases sodium excretion and increases blood pressure by antagonizing dopamine D1-like receptors in renal proximal tubules 2. The receptor is also implicated in metabolic regulation, with genetic variants showing strong associations with BMI and obesity risk 5. In disease contexts, NPFFR2 demonstrates clinical relevance through compound heterozygous variants associated with severe preeclampsia 6 and upregulation linked to poor survival in epithelial ovarian cancer, where NPFF stimulates cancer cell invasion through ERK1/2-mediated MMP-9 upregulation 7. These findings establish NPFFR2 as a potential therapeutic target for hypertension, metabolic disorders, and certain cancers.