GPR20 is an orphan class-A G protein-coupled receptor located on chromosome 8.3 that constitutively activates Gi proteins without a known endogenous ligand, suppressing cyclic AMP 1. Structurally, GPR20 possesses a uniquely folded N-terminal helix cap that stabilizes its basal signaling activity 12. This activation mechanism involves allosteric signaling between extracellular and intracellular domains, requiring both the N-terminal cap and Gi protein coupling 2. Clinically, GPR20 shows selective expression in gastrointestinal stromal tumors (GIST) across all treatment lines regardless of KIT/PDGFRA genotypes, making it a novel therapeutic target for TKI-resistant disease 3. The antibody-drug conjugate DS-6157a targeting GPR20 demonstrated tumor shrinkage in preclinical GIST models resistant to imatinib, sunitinib, and regorafenib 3, though Phase I trials showed lower-than-anticipated efficacy with tumor shrinkage in only 20.6% of patients 4. Beyond oncology, GPR20 participates in reproductive and metabolic pathways. In early-onset preeclampsia, the Siglec-6/GPR20 regulatory pathway promotes mitochondrial dysfunction in trophoblasts 5. Additionally, GPR20 is identified as a druggable GPCR target in pre-menopausal ovarian tissue for fertility management applications 6, and its expression is associated with altered lipid metabolism in metabolic-associated fatty liver disease 7.