The Emerging Role of Olfactory Receptors: From Genomics to Precision Medicine.

Olfactory receptors (ORs), once considered peripheral to sensory biology, are now recognized as functionally important components of precision medicine. This review synthesizes genomic, structural, and translational evidence demonstrating that ORs act as context-dependent molecular sensors influencing metabolism, immunity, neurological function, cardiovascular regulation, and cancer. Extensive genomic diversity within the OR gene family, including single nucleotide variants, copy number variation (CNV), and pseudogenization, drives interindividual differences in receptor function and signaling, providing a mechanistic basis for personalized chemosensory and physiological phenotypes. Beyond the olfactory epithelium, ORs are ectopically expressed across diverse tissues, including the gut, brain, skin, vasculature, immune system, and tumors. In these settings, ORs engage canonical and non-canonical G-protein-coupled receptor (GPCR) signaling pathways to regulate processes such as wound repair, vascular tone, cell proliferation, apoptosis, immune modulation, and barrier function. Collectively, these observations establish ectopic ORs as active signaling components rather than passive expression markers, supporting their potential utility as functional biomarkers and therapeutic targets. Despite growing biological and clinical relevance, translational progress remains limited by incomplete receptor annotation, a large proportion of orphan receptors, and the complexity of mapping ligand-receptor relationships across tissues. This review also highlights emerging strategies addressing these challenges, including high-throughput functional assays, multi-omic and spatial transcriptomic profiling, and artificial intelligence (AI)-enabled models that accelerate ligand prediction, receptor deorphanization, and genotype-phenotype mapping. The development of OR-based biosensor platforms capable of real-time chemical detection further underscores their diagnostic and translational potential. At the population level, substantial variation in OR allele frequencies across ancestries introduces both opportunities and challenges for precision medicine. Accordingly, ethical considerations related to population stratification, data privacy, and equitable implementation are discussed. Together, the evidence reviewed positions ORs as a tractable and clinically promising receptor family that bridges chemosensory biology with individualized diagnostics, therapeutic targeting, and biosensor-guided interventions in precision medicine.