GPR78 is an orphan G protein-coupled receptor that exhibits constitutive activity and couples to Gαs proteins to elevate intracellular cAMP levels 1. The receptor contains an atypical glutamine residue in place of the conserved arginine in the DRY box, suggesting it activates G proteins through a distinct mechanism compared to other group 1 GPCRs 1. GPR78 plays significant roles in cancer progression, particularly in lung cancer where it promotes cell migration, invasion, and metastasis through activation of the Gαq-RhoA/Rac1 pathway 2. The receptor also regulates autophagy and contributes to chemotherapy resistance in non-small cell lung cancer, with knockdown of GPR78 increasing sensitivity to cisplatin and enhancing apoptosis 3. Additionally, GPR78 is targeted by miR-936, which improves cisplatin sensitivity by inhibiting the Galphaq Rho GTPase pathway 4. In Sjögren's disease, GPR78 overexpression in male patients is associated with salivary gland dysfunction through lysosomal dysfunction and caspase-dependent apoptosis 5. The gene has also been implicated in psychiatric disorders, with variants showing association with bipolar disorder and schizophrenia in Scottish populations 6, and longevity studies have identified GPR78 variants associated with survival outcomes 7.