GPR151 is a proton-sensing G-protein coupled receptor that plays critical roles in metabolic regulation, pain modulation, and addiction vulnerability 1. The receptor is highly conserved across mammals and exhibits distinct expression patterns in the habenula complex, spinal cord neurons, and dorsal root ganglia 1. In metabolic pathways, GPR151 regulates hepatic gluconeogenesis as a fasting- and glucagon-responsive gene, with knockout mice showing suppressed gluconeogenesis and reduced hepatic glucose production 2. Loss-of-function variants in GPR151 are associated with lower BMI and reduced type 2 diabetes risk in humans 32. In pain processing, GPR151 is upregulated after nerve injury and modulates neuropathic pain by coupling with P2X3 ion channels to promote neuronal hyperexcitability and microglial activation 4. The receptor also controls nicotine addiction vulnerability through its enrichment in the habenula, where it regulates synaptic plasticity by coupling to Gαo1 protein to reduce cAMP levels 5. Conditional knockout of Gpr151 in nociceptive neurons alleviates neuropathic pain without affecting normal pain sensation, while habenular deletion reduces nicotine behavioral responses but increases drug self-administration 45. These diverse functions position GPR151 as a promising therapeutic target for metabolic disorders, pain management, and addiction treatment.