Introduction

Olfactory receptors (ORs) are primarily expressed in olfactory tissues and are responsible for olfactory sensing. In the human genome, the ORs represent the largest gene family, comprising approximately 400 functional genes and 600 nonfunctional pseudogenes [1]. Most ORs are orphan receptors, and their specific ligands remain unidentified. Only a subset of ORs contains known ligands. Owing to the large number of ORs with unknown ligands, many of their physiological functions remain unclear. As representative G-protein coupled receptors with seven transmembrane domains, ORs are difficult to express ectopically and to purify for structural determination, which poses challenges in understanding their exact functions. Nevertheless, the structures of certain ORs have been reported, revealing their ligands and associated functions [2,3].

Recent studies have increasingly demonstrated the expression of ORs in non-olfactory tissues, sparking active research into their newly discovered roles beyond olfactory sensing [4-6]. ORs in non-olfactory tissues may have various other functions. This review presents the current studies on several ORs expressed in non-olfactory tissues implicated in disease. There is a growing need for further research to uncover novel functions of these receptors.

Roles of ORs in cancer

Research on the correlation between ORs and diseases has been extensively conducted for cancer [7,8]. Specific examples of how ORs play a role in cancer development and metastasis are detailed below.

1. Prostate cancer

Prostate cancer is one of the most extensively studied cancers related to ORs function. Independent studies have reported that activation of OR51E1 and OR51E2 suppresses the proliferation of prostate cancer cells [9,10]. These findings are supported not only by in vitro studies using prostate cell lines but also by in vivo results obtained from mouse models [11]. Additionally, there have been reports indicating overexpression of PSGR2 (prostate-specific G-protein coupled receptor 2), which encodes OR51E1, in prostate cancer samples from patients [12-14]. Conversely, stimulation of OR51E2 enhances the invasiveness and metastasis of prostate cancer, suggesting that stimulation of this OR is associated with cancer progression [15]. Further studies have shown that PSGR promotes intraepithelial neoplasia and enhances the growth of prostate cancer xenografts via the NF-κB (nuclear factor-κB) signaling pathway [16]. Moreover, research has identified a signaling pathway in prostate cancer cells where OR51E2 activates extracellular signal-regulated kinase (ERK) 1 and 2 through the Golgi-localized Gβγ-PI3K (phosphoinositide 3-kinase) pathway [17]. Another report suggested that PSGR may serve as a potential biomarker for prostate cancer detection in urine samples [18].

2. Breast cancer

Several ORs are overexpressed in association with breast cancer development, and recent studies have increasingly focused on elucidating their functions. OR2B6 has been identified as overexpressed in breast cancer in several studies [7,19,20]. Notably, a previous study used single-cell transcriptome analysis to demonstrate the overexpression of OR4F17, OR8B8, and OR8H1 in breast cancer, depending on the differentiation state of cancer cells [7]. Another study on invasive breast carcinoma reported the expression levels of OR2W3 and OR2T8 [20]. OR2T6 has been implicated in promoting breast cancer progression by initiating epithelial-mesenchymal transition through the activation of the MAPK (mitogen-activated protein kinase)/ERK signaling pathway [21]. In a study using an MCF-7 breast cancer cell line, a ligand targeting OR6M1 was identified, and its modulation of OR6M1 activity was shown to regulate cancer cell viability [22]. Moreover, a direct report indicated that OR5B21 drives breast cancer metastasis [23]. Collectively, these findings suggest that OR expression increases in breast cancer as the disease progresses, and that modulation of OR activity is closely linked to cancer cell metastasis.

3. Lung cancer

The cells of the respiratory tract are in direct contact with the surrounding air. Because odors are easily accessible to these cells, ORs are potential targets for lung cancer treatment. A previous study showed that OR2J3 is expressed in A549, a non-small cell lung cancer cell line, and OR signaling is activated by treatment of OR2J3 agonist helional. The stimulation of helional induces apoptosis and inhibits cancer cell proliferation. The authors suggested the possibility of an OR as a putative therapeutic target [24]. Another study demonstrated the expression of OR51E2 in somatostatin receptor-negative lung carcinoids using reverse transcription polymerase chain reaction and immunohistochemistry [25].

4. Other cancers

Extensive studies have explored the relationship between OR51E2 and various types of cancers. OR51E2 expression has been confirmed in human primary melanoma, and reports have suggested a direct link to melanoma metastasis. In addition, single-cell RNA-seq revealed melanoma enrichment of OR1A1. In colorectal cancer cells, OR51B4 activation has been shown to inhibit cancer cell proliferation and induce apoptosis. OR7C1 has been identified as a marker of colon cancer-initiating cells. Furthermore, OR10H1 expression in human urinary bladder cancer has been observed, prompting related studies. OR51E1 has been studied for its potential role as a novel marker in neuroendocrine carcinoma, with reports indicating that exposure to nonanoic acid, a candidate ligand for OR51E1, alters the neuroendocrine tumor phenotype.

Roles of ORs in other diseases

1. Atherosclerosis

In a paper published in 2022 by Orecchioni et al. [26] at the University of California San Diego in Science, the mouse OR Olfr2 (analogous to human OR6A2) was shown to detect its ligand, octanal, in vascular macrophages. This detection activates the NLRP3 (NLR family pyrin domain containing 3) inflammasome and induces interleukin (IL)-1β secretion, thereby contributing to the development of atherosclerosis. This study demonstrated that boosting octanal levels exacerbated atherosclerosis, whereas genetic targeting of Olfr2 significantly reduced atherosclerotic plaque formation. These findings suggest that OR6A2 may be a novel target for the prevention and treatment of atherosclerosis.

2. Skin-related diseases

OR2AT4 has been reported to play a functional role in human keratinocytes. In a 2018 study by Cheret et al. [27] published in Nature Communications, OR2AT4 was shown to be expressed in the epithelium of human hair follicles and, specific stimulation by its ligand, sandalwood odorant, sustained hair growth ex vivo. This effect was linked to the inhibition of apoptosis and increased insulin like growth factor-1 production. Additionally, OR2AT4 in keratinocytes has been implicated in re-epithelialization during wound healing [28]. Recent research by Kim et al. [29] demonstrated that activation of OR2AT4 by the ligand sandalore suppressed the senescent cell phenotype induced by reactive oxygen species in keratinocytes, highlighting its potential as a target for anti-aging therapies in human skin.

3. Alzheimer’s disease

Impairment of the choroid plexus (CP) function is a major pathogenic factor in Alzheimer’s disease (AD). Recent studies have identified strongly induced mRNA expression of OR2K2 in the CP epithelial cells of patients with AD at early Braak stage I, compared to healthy age-matched controls. This finding suggests that OR2K2 may play a role in disease mechanisms related to CP dysfunction in the early stages of AD [30].

4. Viral infection

In a 2019 PNAS study, E et al. [31] demonstrated through CRISPR/Cas9 screening that OR14I1 serves as a receptor for human cytomegalovirus (HCMV) infection. This OR is involved in viral attachment, entry, and infection of epithelial cells. This study also showed that the N-terminal peptide of OR14I1 blocked HCMV entry. There is another report on the relationship between viral infection and OR expression. A recent study reports that coronavirus disease (COVID-19)-induced anosmia is caused by reduced expression of ORs [32]. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can lead to a reorganization of nuclear architecture in olfactory sensory neurons, even though the virus does not directly infect these cells. This non-cell-autonomous disruption results in significant downregulation of OR genes. In experiments with hamsters and human tissue samples, the authors observe that SARS-CoV-2 infection reduces OR gene activity and alters the organization of nuclear compartments responsible for OR expression. These changes may help explain the persistent anosmia experienced by many COVID-19 patients [32].

5. Lung disease

In primary human bronchial epithelial cells and A549 cells, OR2AT4 and OR2J3 were detected. Stimulation of OR2J3 cells with cinnamaldehyde decreased IL-8 levels, reduced proliferation, and slowed wound healing. In contrast, the stimulation of OR2AT4 with Brahmanol enhanced wound healing. Based on this phenotype, this study suggested that ORs could be potential drug targets for the treatment of lung diseases without type 2 inflammation [33].

6. Rare disease

Recent research reported that a rare variant of OR11H1 (OR11H1-A63) is significantly associated with Vogt-Koyanagi-Harada (VKH) disease, a severe autoimmune disease, based on genomic studies [34]. This study also indicated that the missense mutation in OR11H1-A63 might increase susceptibility to VKH disease in a GADD45G-dependent manner.

ORs in metabolism

Recent studies have suggested that ORs are involved in metabolic processes [5]. Below, several related studies are briefly reviewed.

1. OR1A1

OR1A1 activation by (–)–carvone induces HES-1, a corepressor of peroxisome proliferator-activated receptor-gamma (PPAR-γ) in hepatocytes. In (–)–carvone-stimulated cells, the repression of PPAR-γ reduced the expression of mitochondrial glycerol-3-phosphate acyltransferase, which is involved in triglyceride synthesis. Triglyceride levels and lipid accumulation were reduced in cells stimulated with (–)–carvone, and these effects diminished following loss of OR1A1 function. These results indicated that OR1A1 may modulate hepatic triglyceride metabolism as a non-redundant receptor in hepatocytes [35]. The involvement of OR1A1 in metabolism was confirmed in another study. Kim et al. [36] investigated whether the activation of gut-expressed ORs plays a physiological role. Using a human-derived enteroendocrine L cell line, they discovered that stimulation with the odorants geraniol and citronellal led to glucagon-like peptide-1 (GLP-1) secretion. The knockdown of OR1A1 and OR1G1 eliminated this effect, suggesting that ORs may play a crucial role in increasing GLP-1 secretion.

2. Olfr109

Cheng et al. [37] discovered that Olfr109 is the receptor for the diabetes-associated insulin peptide InsB:9-23. This autonomous sensing of InsB:9-23 by Olfr109 in β-cells inhibits intact insulin secretion and promotes islet inflammation. This study suggested a direct role for OR in beta cells, with a detailed working mechanism.

3. OR2J3

One study found that OR2J3 plays a role in the directed release of serotonin from enterochromaffin (EC) cells. The authors demonstrated the expression of OR2J3 in human EC cells. Helional, an OR2J3-specific agonist, stimulates EC cells to release serotonin, which is mediated by protein kinase G [24].

4. OR10J5

The authors suggested that OR10J5 played a crucial role in lipid accumulation. They showed that α-cedrene, a novel agonist of OR10J5, protected against hepatic steatosis and treatment of α-cedrene significantly reduced lipid contents in human hepatocytes. This phenotype was dependent on OR10J5 [38].

5. OR51E1

OR51E1 influences the secretion of GLP-1 and peptide YY (PYY). The authors confirmed the expression of OR51E1 in intestinal L-cells and observed an increase in GLP-1 and PYY secretion upon treatment with nonanoic acid, a known OR51E1 agonist. This effect was diminished when OR51E1 expression was knocked down using RNA interference, indicating that OR51E1 plays a significant role in regulating secretion [39]. Additionally, OR51E1 expression has been identified in the gastrointestinal tract and is reported to colocalize with enteroendocrine cells [40]. The same study also observed that the expression of OR51E1 was modulated by alterations in the intestinal microbiota, indicating a potential interaction between OR51E1 and gut microbiota dynamics.

Conclusions

As we have discussed, recent studies on the novel roles of ORs expressed in non-olfactory tissues have been actively emerging [2,41-44]. Based on these studies, there are also efforts to develop OR-targeted treatments. There are many reports on which ligands to specific OR have a cure role in disease, for example, using ligand sandalore for OR2AT4 which helps in wound healing and hair growth, has shown positive effects [27]. This suggests that ORs could be important targets for treatments. However, there are still some challenges. One is the complicated relationship between ORs and their ligands. For instance, OR1A1 has over 50 known ligands. This means that more research about specific ligands is needed to understand the relationship between receptors and ligands. Additionally, since ORs have the seven-transmembrane structure, methods for ectopic expression of ORs are not fully established, making it difficult to find ligands efficiently. Despite these challenges, recent efforts to evaluate the structure of ORs increase the potential to identify ligands for specific ORs. Consequently, ORs are anticipated to be potential targets for disease treatment.

Article information

Conflicts of interest

Jaewon Shim is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

Funding

This research was supported by a grant from the Basic Science Research Programs through the National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (grant number: NRF-2017R1C1B2006455 and NRF-2022R1F1A1076324).

Author contributions

Conceptualization: JS. Data curation: IY, JSY. Funding acquisition: JS. Investigation: IY, JSY, JS. Writing - original draft: IY, JSY, JS. Writing - review & editing: JS. All authors read and approved the final manuscript.

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Figure & Data

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