COPD is defined as a common, preventable, and treatable disease characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities, usually caused by significant exposure to noxious particles or gases (13). According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, the post-bronchodilator FEV1/FVC < 0.70 is used to diagnose airflow limitation, which is a key feature of COPD. In addition to pulmonary function tests, imaging studies like chest computed tomography scans are valuable for assessing lung structure changes and disease severity (14). Besides, COPD can be classified into two main phenotypes: chronic bronchitis and emphysema. Chronic bronchitis is characterized by persistent cough and sputum production, while emphysema is manifested as alveolar destruction and airflow limitation. Early identification and intervention of COPD are crucial for improving patients’ quality of life and prognosis. Figuring out how to achieve these is a key aspect that we need to study intensively in the next step.

The pathogenesis of COPD is multifactorial and involves complicated interactions between environmental factors, immune responses, and genetic susceptibility (1). Environmental factors like smoking, biomass fuel exposure, occupational dust, chemical exposure, and air pollution are major precipitating factors for COPD development. These noxious agents cause chronic inflammation and oxidative stress in the lungs, leading to tissue damage and remodeling. The immune response in COPD is dysregulated, with the activation of multiple immune cells, such as neutrophils, macrophages, lymphocytes, and eosinophils (15). These cells secrete a plethora of inflammatory mediators and cytokines, including interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and chemokines, which can recruit more immune cells to the lungs, perpetuating the inflammatory process and contributing to airway remodeling and lung tissue destruction. Genetic factors also play a role in COPD susceptibility. Mutations in the SERPINA1 gene, which encodes alpha-1 antitrypsin, are the most well-characterized genetic risk factors, leading to hereditary alpha-1 antitrypsin deficiency (AATD) (16). However, other genetic variations associated with COPD, such as those related to alpha1-antichymotrypsin, alpha2-macroglobulin, and vitamin D-binding protein, are still under investigation (17). Additionally, multiple pathogenic mechanisms—including recurrent infections, mucus hypersecretion, and microbial dysbiosis—contribute differentially to COPD development. Notably, chronic airway inflammation and subsequent tissue remodeling triggered by diverse factors remain central to disease pathogenesis.

While the pathogenesis of COPD is well-established to involve chronic inflammation, oxidative stress, and airway remodeling, current therapeutic strategies remain insufficient to halt disease progression. Intriguingly, emerging evidence suggests that ORs may directly participate in COPD pathogenesis by regulating immune cell activation, inflammatory cytokine release, and smooth muscle dynamics. For instance, activation of OR2AT4 in alveolar macrophages reduces IL-6 and C-X-C motif chemokine ligand 8 (CXCL-8) secretion, thereby highlighting ORs’ anti-inflammatory role in the disease microenvironment (18); activation of OR2W3 in airway smooth muscle cells promotes relaxation through Ca²⁺ influx (6). Conversely, aberrant activation of OR1D2 in airway smooth muscle cells enhances contraction via Ca²⁺ influx, potentially exacerbating airflow limitation (19). These findings suggest that ORs extend beyond their canonical role in odor detection, forming a dynamic interaction network with core COPD pathways through non-canonical signaling.

Olfactory receptors belong to the superfamily of G protein-coupled receptors (GPCRs), which are integral membrane proteins with seven transmembrane helices. In mammals, the OR gene family is one of the largest GPCR families, with approximately 370 genes in humans (20). ORs are predominantly expressed in the olfactory epithelium, where they function as chemo-sensors to detect a vast array of odorant molecules. The structural diversity of olfactory receptors enables them to recognize and discriminate thousands of different odorant molecules, thus playing a vital role in olfactory perception. Their ligands can be classified into several categories of chemical substances based on their chemical structures, including alcohols, aldehydes, acids, and esters (21).

Beyond the olfactory system, ORs have been detected in various non-olfactory tissues, including the respiratory tract, digestive system, skin, and immune cells (22–25). In these tissues, ORs are involved in a wide range of physiological and pathological processes. For example, in macrophages, ORs can modulate the inflammatory response (26). Activation of certain ORs in macrophages has been shown to exacerbate atherosclerosis (25) and promote tumor progression (27). In the skin, ORs are involved in hair growth (28) and wound healing (8). In the digestive system, they participate in glucose metabolism (29).

Generally speaking, how do olfactory receptors function? The binding of ligands to ORs activates a G-protein, typically Gαolf, which in turn activates adenylate cyclase (AC), leading to an increase in intracellular cyclic adenosine monophosphate (cAMP) levels. cAMP then activates cyclic nucleotide-gated cation channels (CNG channels), causing an influx of calcium ions (Ca²⁺) into the cells. The Ca²⁺ influx triggers a series of downstream signaling pathways (18, 25). The signal transduction mechanisms of ORs in non-olfactory tissues are similar to those in the olfactory epithelium but also have different downstream effects depending on the cell types. In addition to the cAMP-dependent pathway, ORs can also activate other signaling cascades, such as the phosphatidylinositol 3-kinase (PI3K)-Akt pathway and the mitogen-activated protein kinase (MAPK) pathway, which regulate cell survival, proliferation, migration, and differentiation (8, 30).

In recent years, remarkable progress has been made in molecular biology research on ORs. Through genomic and bioinformatics approaches, researchers have identified and annotated numerous OR genes, particularly in vertebrates. These studies have provided critical insights into the evolution and functions of ORs (31). Structural biology techniques, such as X-ray crystallography and cryo-electron microscopy, are instrumental in determining the three-dimensional structures of ORs bound to their ligands. These structural studies have elucidated the molecular mechanisms of ligand-receptor interactions, which are essential for developing novel drugs targeting ORs (32). Furthermore, functional genomics approaches, including gene knockout and overexpression studies in animal models, have helped clarify the physiological roles of specific ORs (25). These findings have laid a solid foundation for understanding the role of ORs in health and disease and for advancing targeted therapies.

In modern daily life, individuals are exposed to a diverse range of odorants from various sources, many of which are ligands for ORs ( Table 2 ). Notably, patients with COPD have been found to exhibit elevated levels of volatile organic compounds (VOCs) in their exhaled breath compared to healthy individuals. These VOCs, such as benzaldehyde, isoprene, hexanal and nonanal, are promising candidates for COPD biomarkers. Specifically, increased levels of nonanal are associated with smoking behavior (33, 34).

As major risk factors for COPD, cigarette smoke and air pollution contain various ligands for ORs, including nonanal, cinnamaldehyde and hexanal (35–38). Nonanal and cinnamaldehyde have been shown to promote the secretion of inflammatory cytokines, such as IL-6 and IL-8 (39, 40), which are key mediators in the pathogenesis of COPD. Aromatic products, including cosmetics, can release odorants that may interact with ORs in the respiratory tract. Although the effects of these products on the respiratory system are not fully understood, skin contact-induced inflammatory reactions suggest potential influence on the respiratory tract (41). As is known to all, the respiratory tract and the gut are colonized by microbiota. Their metabolites, such as acetate and propionate, also act as ligands for ORs (42, 43). Additionally, endogenous metabolism, particularly lipid peroxidation, generates various aldehydes, including hexanal, octanal, and farnesol, which can also bind to ORs in the respiratory tract (44). These ligands can influence the activity of ORs in airway cells, potentially influencing COPD development and progression through mechanisms such as chronic inflammation and airway remodeling.

In recent years, research into the role of ORs in obstructive lung diseases, particularly COPD, has gained momentum. Jürgen Knobloch’s research group successfully isolated and cultured primary bronchial epithelial cells from non-COPD patients, demonstrating that these cells functionally express four specific ORs: OR51B5, OR1G1, OR2AT4, and OR2J3 (39, 40). Farnesol, isononyl alcohol and nonanal can activate these ORs respectively, and influence the secretion of inflammatory cytokines IL-6 and IL-8, which suggests that ORs have a potential role in airway inflammation. Human airway smooth muscle cells (HASMCs) play a crucial role in airway remodeling, a hallmark feature of COPD. Additionally, several research teams have isolated HASMCs and identified the expression of various ORs, including OR2W3, OR51E2, OR2AG1, and OR1D2 (5, 6, 19).

Weidinger D et al. conducted a study on alveolar macrophages isolated from patients with COPD, asthma, or chronic bronchitis, and demonstrated significant expression of olfactory receptors OR2AT4 and OR1A2 (18). Activation of these receptors was found to reduce the secretion of pro-inflammatory cytokines and inhibit inflammation induced by lipopolysaccharide (LPS), lipoteichoic acid (LTA), or peptidoglycan (PGN). Additionally, pulmonary neuroendocrine cells (PNECs), despite their low abundance in the lung, have been shown to increase in number in COPD patients, with a concurrent upregulation of OR2W1 receptor expression in these cells. This finding suggests a potential role of OR2W1 in neurotransmitter secretion and airway regulation (45).

While these findings are promising, current clinical research still has several limitations. The experimental designs are often not rigorous enough, with many studies relying solely on LPS stimulation without considering the combined effects of cigarette smoke extract (CSE) and other relevant factors. Besides, sample sizes are relatively small, and there is a lack of multi-center randomized controlled trials (RCTs). These limitations restrict the generalizability and reliability of the results, underscoring the need for more comprehensive and well-designed studies.

In COPD animal models, research on ORs is still in its early stage. Nevertheless, some studies have demonstrated that treatment with the OR agonist farnesol can protect the lungs from cigarette smoke-induced damage in COPD-like animal models (46). Farnesol exerts its protective effects by inhibiting pulmonary inflammation, reducing oxidative stress, and enhancing antioxidant capacity. Li, Tay, and colleagues utilized microarray and q-PCR to evaluate the expression of ORs in airway and pulmonary macrophages of mice treated with IFN-γ, LPS, or IFN-γ/LPS. Their findings identified a group of ORs (OR65, OR272, OR352, OR446, OR568, OR622, OR657, and OR1014) that were expressed in mouse airway and pulmonary macrophages and were significantly upregulated under IFN-γ/LPS treatment. Furthermore, stimulation with octanal (an agonist of ORs) promotes the release of monocyte chemoattractant protein-1 (MCP-1) and enhances macrophage chemotaxis, leading to increased immune cell infiltration and exacerbated local inflammation (47).

Animal model studies have demonstrated the potential of ORs in the pathogenesis of COPD-like conditions and have identified promising therapeutic targets. However, further research is required to fully harness these findings and translate them into clinical applications.

Accumulating evidence have highlighted the crucial role of the lung microbiota in both healthy and disease states (78–81). In healthy individuals, the lungs host a diverse microbiota, primarily composed of Prevotella, Streptococcus, Veillonella, Fusobacterium and Haemophilus (79–81). However, in disease conditions such as COPD, the microbiota balance is disrupted, characterized by a shift in the composition and abundance of bacteria. In asthmatic patients, the lung microbiota is dominated by Haemophilus, Moraxella and Neisseriaceae, with notable increases of Haemophilus, Staphylococcus, Pseudomonas and Actinomyces (82–84). In COPD patients, Pseudomonas, Streptococcus, Prevotella and Haemophilus are the predominant components, with a marked increase in Pseudomonas aeruginosa, Lactobacillus, Proteobacteria and Haemophilus (85–87). Bacterial components and their metabolites can act as ligands for ORs (88, 89). For instance, diaminopimelic acid, a component of the cell wall of gram-negative bacteria (90), induces the release of MCP-1 in mouse lung macrophages, exacerbating lung inflammation (47). Additionally, 12 types of VOCs, including heptane and methylated cycloalkanes, were identified and they are generated by cultures of bacteria and viruses associated with respiratory infections (43). How these microorganisms affect the occurrence and progression of COPD, and how cells in the lung tissue sense these factors that may induce lung injury remain to be further explored. ORs may be one of the potential mechanisms. Future research should focus on elucidating the complex interplay between the lung microbiota, ORs, and COPD development, which may open new avenues for therapeutic interventions targeting the microbiota-OR axis.

The gut-lung axis represents a bidirectional communication system between the gut microbiota and the respiratory system. SCFAs, produced by the fermentation of dietary fibers by gut microbiota (91), can reach the lungs via the bloodstream and modulate pulmonary inflammatory responses (65, 92–95). Given that many SCFAs are agonists or antagonists of ORs (5, 69, 96), ORs may play a key role in facilitating communication within the gut-lung axis. Understanding how ORs respond to SCFAs in the context of the gut-lung axis could provide insights into the development of novel therapeutic strategies for COPD. For example, modulating the gut microbiota to increase the production of beneficial SCFAs or developing drugs that target specific ORs activated by SCFAs may offer innovative approaches to regulate airway inflammation and remodeling in COPD patients. However, further research is required to clarify the precise mechanisms by which ORs mediate the effects of SCFAs on the respiratory system.

Approximately 40% of available drugs target GPCRs (97). As the largest subgroup within the GPCRs family, ORs hold significant promise for drug development. Recognizing ORs as potential regulators of pulmonary inflammatory diseases such as COPD, provides new opportunities for therapeutic intervention. Synthetic OR agonists and antagonists can be designed to selectively modulate the mechanisms in COPD, potentially reducing inflammation, preventing airway remodeling and improving lung function.

However, several challenges must be addressed before OR-based therapies can be translated into clinical practice. Among these challenges, one major obstacle is the lack of receptor-ligand specificity. ORs can interact with multiple ligands, and ligands can bind to multiple receptors. Besides, Conventional small-molecule agonists/antagonists often cause off-target effects due to the widespread expression of ORs in extrapulmonary tissues (e.g., heart and kidneys). Ensuring the specificity of receptor-ligand interaction is crucial to minimize off-target effects. Comprehensive mapping of OR ligand profiles and the development of targeted drug delivery systems are essential to overcome this challenge. On one hand, we should continue developing agonists/antagonists with higher specificity. Current studies have confirmed that Corilagin attenuates atherosclerosis by inhibiting Olfr2 signaling (98). On the other hand, we can develop ORs-related nanomaterials to enhance tissue targeting, cell targeting, and receptor targeting. Meanwhile, future research should also focus on understanding the precise distribution of ORs in different cell types and tissues within the lung, mapping the complex signal transduction networks they are involved in, and elucidating their functions in the COPD pathophysiology.

Nevertheless, despite advances in single-cell RNA sequencing and spatial transcriptomics, detecting low-abundance ORs remains challenging due to their minimal transcript levels. We look forward to the availability of more sensitive high-throughput sequencing methods in the future to aid in the identification of specific expression of ORs in the lungs, new OR ligands and the development of more effective drugs. These efforts may not only expand our understanding of the olfactory system but also facilitate the development of innovative treatment strategies for COPD and other respiratory diseases.