Orphan G-protein coupled receptor 75 (GPR75), a unique and controversial potential therapeutic target.

G protein-coupled receptors (GPCRs) are a large and diverse superfamily of membrane proteins that mediate cellular responses to a wide range of stimuli, making them critical players in a variety of physiological and pathological processes. Despite their recognized therapeutic potential, many GPCRs are still considered orphans, their ligands and biological functions remaining unknown. Among these, GPR75 has garnered increasing attention due to its high expression in the brain and retina and its proposed roles in cardiovascular function, metabolism, and cancer. Recent studies have suggested several potential endogenous ligands for GPR75, including 20-HETE and RANTES/CCL5, but their status as true receptor agonists remains controversial. Here, we summarize the current state of knowledge regarding GPR75, from its discovery and evolutionary context to its expression profile, putative ligands, and emerging physiological functions. Understanding the role of GPR75 may offer new therapeutic avenues for neurological disorders, metabolic diseases, and cancer.