Extra-nasal odorant receptors: molecular mechanisms and therapeutic implications

Since the first demonstration of extra-nasal odorant receptor (OR) function of OR1D2 (hOR17-4) in human sperm, ORs have emerged as a widely distributed receptor family. ORs are now known to be belonged to a family of seven transmembrane domain G protein-coupled receptors (GPCRs) expressed across diverse extra-nasal tissues, including skin, gastrointestinal tract, kidneys, cardiovascular system, liver, immune cells, and tumors. In these tissues, ORs act as metabolite- and environment-sensitive sensors that translate chemical cues into tissue-specific signaling pathways that regulate proliferation, differentiation, metabolic homeostasis, and immune responses among others. Dysregulated ORs signaling is increasingly linked to cancer, metabolic, and impaired tissue repair, thereby constitute potential therapeutic targets. Recent advances in cryo-electron microscopy provide near-atomic structural insights into human ORs structure-function, revealing conserved activation mechanisms and ligand-binding features. In parallel, AI-driven molecular dynamics simulation, single-cell transcriptomics, and high-throughput deorphanization platforms are rapidly expanding the OR-ligand landscape. This review integrates current progress in ORs structures and signaling, and outlines key opportunities and challenges for translating extra-nasal ORs structure-function into clinical applications.