NPFF (neuropeptide FF-amide peptide precursor) encodes a neuropeptide with diverse physiological functions, particularly in blood pressure regulation and immune modulation. NPFF acts through two G-protein coupled receptors (NPFFR1 and NPFFR2) that primarily couple to Gαi/o signaling, inhibiting cAMP production 1. In renal proximal tubule cells, NPFF decreases forskolin-stimulated cAMP production and antagonizes dopamine D1-like receptor signaling, with renal NPFF infusion reducing sodium excretion and increasing blood pressure 2. The peptide plays a crucial role in neutrophil polarization during bacterial infection, where the Mrgpra1-NPFF axis promotes anti-inflammatory neutrophil states by countering IFNγ-mediated pro-inflammatory polarization 3. NPFF is highly expressed in spinal cord superficial layers and dorsal root ganglia, where it modulates pain processing and is upregulated during peripheral inflammation 4. In colorectal cancer, NPFF promotes metastasis through epithelial-mesenchymal transition via JAK2/STAT5 signaling and macrophage polarization toward protumorigenic M2-like phenotypes 5. NPFF-positive cells are distributed throughout human cerebral cortex and white matter, with reduced numbers observed in neurodegenerative diseases including ALS, Alzheimer's disease, and schizophrenia 6.