VIPR1 is a G protein-coupled receptor activated by vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP), with VIP and PACAP27 showing equivalent high affinity 12. Upon ligand binding, VIPR1 triggers intracellular signaling through G proteins and activates cAMP-dependent pathways 13. In cancer contexts, VIPR1 functions as a tumor suppressor across multiple tissue types. VIPR1 overexpression inhibits lung adenocarcinoma cell growth, migration, and invasion 4, while activation by VIP suppresses hepatocellular carcinoma progression by regulating arginine biosynthesis and inhibiting pyrimidine synthesis through mTOR/p70S6K signaling 5. In colon cancer, VIPR1 promotes cuproptosis and inhibits HIF-1α signaling, suppressing proliferation and invasion 6. VIPR1 expression is typically downregulated in HCC and correlates with poor prognosis; epigenetic modifications including promoter methylation and H3K27 deacetylation suppress VIPR1 transcription 7. Beyond cancer, VIPR1 mediates immune responses—sensory neuron-derived VIP signals through VIPR1 on B cells to regulate antibody production during bacterial infection and asthma 8. In intestinal homeostasis, epithelial VIPR1 acts as a neuronal checkpoint restraining intestinal stem cell proliferation via ERK-Notum-Wnt/β-catenin inhibition; VIPR1 deletion enhances mucosal regeneration in colitis 9. VIPR1 is identified as a novel FTLD-TDP subtype-specific risk gene 10.