1. Introduction
Over the past two decades, the rapid aging of the population has led to a 30% increase in the prevalence of OSA (1). Epidemiological research estimates that ~936 million adults aged 30-69 globally are affected by OSA, with a prevalence of ~22% in males and 17% in females (2). The COVID-19 pandemic has further exacerbated the incidence of OSA (3), solidifying its status as a common sleep-related breathing disorder in clinical settings (4). OSA is characterized by recurrent obstruction of the upper airway during sleep, leading to periodic hypoxemia, disturbances in sleep continuity and increased respiratory effort. OSA is characterized by intermittent hypoxia during sleep, which activates HIF-1. This activation leads to oxidative stress, damaging cellular components such as DNA, proteins and lipids. The repeated cycles of hypoxia and subsequent oxidative stress create an environment conducive to genetic alterations that may drive the malignant transformation of lung cells (5). OSA triggers a systemic inflammatory response. The intermittent hypoxia and sleep fragmentation associated with OSA activate the sympathetic nervous system, releasing pro-inflammatory cytokines such as IL-6, TNF-α and high-sensitivity C-reactive protein (hsCRP). Chronic inflammation disrupts normal cellular functions and tissue homeostasis, fostering an immunosuppressive microenvironment in the lungs that allows cancer cells to evade immune surveillance and elimination. In addition, inflammatory mediators can directly stimulate cell proliferation and angiogenesis, both crucial for tumor growth and metastasis (6). OSA is linked to significant metabolic changes, disrupting normal lipid metabolism and leading to abnormal lipid profiles, while also affecting glucose metabolism, resulting in insulin resistance and elevated blood glucose levels. These metabolic alterations create a favorable environment for cancer cells to thrive, as hyperglycemia provides an abundant energy source and can stimulate growth factor production (7,8). Notably, OSA has been emerged as a new risk factor for lung cancer (9) and is known to disrupt normal lipid metabolism (10,11).
A hallmark molecular feature of hypoxia in OSA is the upregulation and stabilization of HIF-1 (12-14), a critical genomic mediator of cellular adaptation to low oxygen levels. HIF-1 plays an essential role in regulating inflammatory pathways by modulating inflammatory responses, particularly preventing excessive reactions. In addition, it is associated with the regulation of genes such as MCAD and LCAD, both of which are involved in lipid metabolism. Recent research has highlighted the potential of A2A receptor (A2AR) blockade to disrupt the hypoxia/HIF-1-adenosine immunosuppressive axis, enhancing the effectiveness of cancer immunotherapy (15). Additionally, A2AR is indispensable for tissue protection under hypoxic conditions and for the regulation of lipid metabolism (16).
OSA is mainly mediated by intermittent hypoxia, which leads to low-grade inflammation (17). Adenosine receptors (ARs) have been shown to mitigate hypoxia-induced inflammation, particularly in the context of acute lung injury. During ischemic and hypoxic events, extracellular concentrations of adenosine, a crucial neurotransmitter involved in the immune response, can increase markedly, reaching levels ≤100 times higher than normal. The upregulation of adenosine and the induction of HIF-1 in response to hypoxia are directly linked, suggesting that HIF-1 activation through A2AR may contribute to anti-inflammatory responses and tissue protection. Although persistently elevated adenosine levels appear to trigger the release of inflammatory cytokines, A2AR is predominantly expressed in mature dendritic cells, leading to a reduction in pro-inflammatory cytokines (18). Previous studies have demonstrated that hypoxia activates adenosine signaling via A2AR (19-21). Additionally, the HIF-1/adenosine axis provides protective effects for the lungs during conditions such as acute respiratory distress syndrome, although it may contribute to inflammation and injury in chronic lung diseases (22).
Based on these findings, along with research showing that targeting the hypoxic-A2AR pathway can release anti-tumor T cells with immunosuppressive properties (23), A2AR has emerged as a critical receptor for mediating hypoxia-related tissue protection and regulating HIF-1 due to its anti-inflammatory effects (16). The molecular process by which A2AR regulates HIF-1 involves cytokine interactions and the activation of intracellular pathways such as Protein Kinase C (PKC), ATP-sensitive Potassium Channel (KATP), p38 MAPK and PI3K/Akt (24,25). These intricate networks present a promising therapeutic target for A2AR, particularly through the PI3K/Akt/HIF-1 pathway in the treatment of OSA (Fig. 1). The present study aimed to clarify the current prevalence of OSA and its associated hazards, including intermittent hypoxia, sleep disorders and its role as a risk factor for diseases such as lung cancer. It provided an in-depth exploration of the pharmacological mechanisms of A2AR in OSA, focusing on its effects on inflammation and lipid metabolism related to OSA through the PI3K/Akt/HIF-1 pathway.
4. Discussion
Adenosine, deriving from ATP degradation, mediates its physiological effects through four distinct subtypes of G-protein-coupled receptors named A1R, A2AR, A2BR and A3R. Previous research has shown that hypoxia and inflammation can lead to the accumulation of extracellular ATP/ADP due to the cell membrane damage (129). Consequently, it is important to investigate the pharmacological effects of adenosine receptors in the context of OSA (129-135) (Table I). During sleep apnea, adenosine is released as a response to hypoxia, which can promote sleep and reduce apnea episodes through the activation of A1R/A3R (131) and the inhibition of A2AR (136). High doses of caffeine, a well-known adenosine receptor antagonist, may provide an improved means of apnea management (137). In addition, adenosine plays a role in sensitizing the carotid body during intermittent hypoxia (134). Caffeine has been shown to decrease both baseline and hypoxia-induced (5% O2) chemosensory activity in the carotid sinus nerve of rats with intermittent hypoxia (134). Therefore, blocking adenosine receptors and modulating adenosine metabolism in the carotid body could aid in the management of sleep apnea (135). Other research indicates that increased expression of A2AR during hypoxia may help protect cells from the damaging effects of low oxygen levels (138). Conversely, A2AR deficiency has been linked to airway inflammation and hyperresponsiveness (139). Mirtazapine, a prescription drug that acts as an A2AR antagonist, appears to be ineffective in markedly improving sleep apnea and may even contribute to weight gain, potentially worsening OSA (140). There is speculation that appropriate use of A2AR agonists could inhibit the PI3K/Akt pathway, indirectly reducing the expression of HIF-1 and pro-inflammatory cytokines while enhancing lipid metabolism. Notably, the inhibitory effect of A2AR activation on respiratory drive appears to vary with age. Thus, further research is needed to clarify the pharmacological effects of A2AR in the treatment of OSA and clinical trials should be conducted to explore its potential therapeutic applications.
Intermittent hypoxia in OSA can contribute to inflammation-related cardiac metabolic diseases, with vascular inflammation and remodeling linked to increased leukocyte-endothelial cell interactions and T cell activation. While HIF-1 is expressed in unstimulated cells, NECA (an A2AR agonist) does not enhance HIF-1 mRNA expression in the absence of LPS stimulation. This indicates that LPS-induced A2AR expression crucial for the LPS/NECA-mediated upregulation of HIF-1. The NF-κB pathway is influenced by HIF-1, acting as a potent inflammatory activator that drives the release of TNF, IL-6, IL-8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 (MCP-1). Although OSA is hypothesized to elevate ROS levels, more evidence is necessary to fully support this (141). HIF-1 regulates the expression of various factors, including EPO, VEGF, inducible nitric oxide synthase and heme oxygenase, along with molecules involved in glucose metabolism, mitochondrial function and cellular adaptation to intermittent hypoxia during oxidative stress. Inhibition of HIF-1 reduces the expression of VEGF and Bcl2 interacting protein 3, thereby protecting against delayed cell death. Notably, the protective effects mediated by the PI3K/Akt and HIF-1 pathways may be reversed in the hypoxic microenvironment of cancer, highlighting the regulatory role of A2AR on HIF-1 as a potential therapeutic target for OSA. Intermittent hypoxia can downregulate endothelial nitric oxide synthase and enhance endothelin-1 production through the Erk1/2 pathway, while also increasing phosphorylation via the PI3K/Akt pathway, leading to endothelial dysfunction (142). Beyond the influences of inflammation and lipid metabolism, further investigation into the pharmacological effects of the PI3K/Akt/HIF-1 pathway on glucose metabolism, mitochondrial function and cell apoptosis in relation to OSA is warranted.
In addition, repeated exposure to hypoxic conditions can lead to significant alterations in gene transcription and post-translational protein modifications, resulting in changes in plasma concentrations of lipids, proteins and other biological compounds (143). The advent of large metabolomic datasets has enabled the use of metabolites as biomarkers for disease progression (46). Research indicates that the pathogenesis of cardiovascular disease and metabolic complications associated with OSA may be markedly linked to specific metabolic changes. Mendelian randomization studies have identified associations between OSA and >10 metabolites, including the plasma metabolite 3-Dehydrocarnitine. The biosynthetic pathway of valine, leucine and isoleucine is implicated in OSA pathogenesis (144). However, there is a lack of exploration into how inflammation alters metabolic pathways in the development of OSA and its complications. Therefore, understanding the involvement of metabolites in inflammation is critical for unraveling OSA pathogenesis and identifying potential therapeutic targets (145).
In the clinical management of OSA, a variety of treatment approaches are currently available, each with its own distinct characteristics and implications. These treatment modalities primarily encompass continuous positive airway pressure (CPAP), oral appliance therapy, surgical interventions, lifestyle changes, drug treatment and hypoglossal nerve stimulation. CPAP is effective for moderate to severe OSA, improving symptoms and quality of life, but requires maintenance and can be uncomfortable (146,147). Oral appliances are portable and work well for mild OSA, though less effective for severe cases and may cause discomfort (148). Surgical options, such as uvulopalatopharyngoplasty, offer long-term benefits for patients with clear anatomical issues but carry risks and long recovery times (149,150). Lifestyle changes complement treatments with no major side effects, though their impact is gradual (151). Drug treatments may help mild OSA but are generally limited (152-154). Hypoglossal nerve stimulation is a less invasive alternative to CPAP or surgery, with good tolerance but concerns over cost and long-term efficacy (155). Consequently, given the diverse nature of these treatment options for OSA, it becomes of utmost importance to conduct a comprehensive comparison of different treatments for OSA (Table II) Such a comparison can provide valuable insights for healthcare providers and patients alike, enabling them to make more informed decisions regarding the most appropriate treatment approach based on individual circumstances (149).
The relationship between OSA and lipid profiles remains a complex area of study. While some clinical evidence indicates that CPAP devices can improve certain aspects of dyslipidemia by alleviating apnea-hypopnea, much of this data are derived from observational studies. CPAP may lead to reductions in inflammatory cytokines and inhibit lipid peroxidation, as evidenced by decreased levels of malondialdehyde and endothelial lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) (156). However, its effect on oxidized low-density lipoprotein (oxLDL) levels in patients with OSA with comorbidities appears negligible after one year of treatment (157). By contrast, randomized controlled trials assessing the effects of CPAP on lipid metabolism have produced inconclusive results, with two meta-analyses yielding conflicting evidence (57). Large population-based studies generally highlight a relationship between OSA and dyslipidemia; however, they often fail to adequately control for confounding factors such as diet, exercise and the use of lipid-lowering medications, introducing potential biases. Thus, there is a pressing need for new clinical studies with larger sample sizes that account for these variables. Such research should also facilitate the screening of comorbid conditions for more timely interventions, ultimately enhancing patient outcomes.
The use of A2AR agonists presents several limitations and challenges that must be carefully addressed. These agonists may exhibit non-specific effects on other adenosine receptors, potentially leading to side effects, so enhancing their specificity and selectivity is crucial. Additionally, the pharmacological efficacy and pharmacokinetics of A2AR agonists can impact their clinical application, making it essential to optimize drug structure to improve bioavailability, stability and half-life (158). This optimization could enhance efficacy and reduce dosing frequency, contributing to more convenient and effective treatment. Safety and tolerability are paramount, as long-term use of A2AR agonists may result in adverse reactions, particularly in the cardiovascular, digestive and nervous systems. Comprehensive evaluations of safety and tolerability are necessary to establish appropriate dosing and treatment plans (159). Furthermore, given the complex and multifactorial nature of inflammatory diseases, relying solely on A2AR agonists may yield limited effectiveness (160). Exploring combination therapies with other drugs represents a promising avenue for future research, aiming to enhance overall treatment efficacy while minimizing side effects. In addition, individual patient responses to A2AR agonists can vary markedly, making it vital to understand each patient's genetic background, disease subtype and immune status for developing personalized treatment plans, which could substantially improve treatment effectiveness and reduce adverse reactions (161).
The present study made significant contributions to our understanding of OSA and its associated aspects, proving valuable to the scientific community. It explored various elements related to OSA, examining traditional mechanisms such as intermittent hypoxia and sleep disruptions while focusing on adenosine receptors, particularly A2AR. By integrating the effects of A2AR on inflammation, lipid and glucose metabolism, mitochondrial function and cell apoptosis through the PI3K/Akt/HIF-1 pathway, the current review presented a comprehensive view of the complex interactions within OSA. This holistic understanding aids researchers in developing more targeted hypotheses and experimental designs, revealing previously overlooked connections among physiological processes. In contrast to earlier reviews that primarily addressed basic OSA pathophysiology and the effects of intermittent hypoxia on vascular endothelial damage and systemic inflammation (162), the present review offered a deeper analysis of the molecular mechanisms of A2AR and broader implications. It built on this foundation by exploring the regulatory role of A2AR in the PI3K/Akt/HIF-1 pathway and its consequences for inflammation and lipid metabolism, providing a more nuanced perspective on OSA. In addition, the present review emphasized the intricate interplay between inflammation and metabolic changes in OSA. It highlighted how specific metabolites contribute to OSA pathogenesis and how inflammation affects metabolic pathways, addressing an area less explored in prior research. This focused approach encourages further investigation into these interactions, potentially leading to the identification of novel biomarkers for early diagnosis and new therapeutic targets for more effective treatments. By contrast, another previous review centered on the relationship of OSA with cardiovascular diseases, examining how OSA-induced changes in blood pressure, lipid profiles and endothelial function contribute to cardiovascular morbidity (57). While this is an important area, it did not comprehensively address the role of metabolites or the interaction between inflammation and metabolism as our review does. By specifically focusing on these aspects, the present study underscored the significance of understanding metabolite involvement in inflammation, which could reveal new insights into the pathogenesis of OSA and therapeutic opportunities. Additionally, the present review discussed the potential clinical applications of A2AR agonists in treating inflammatory diseases beyond COPD and asthma, highlighting their limitations and challenges. By broadening the scope of the clinical utility of A2AR, it provided critical insights for researchers and clinicians, guiding future research and optimizing the use of A2AR agonists in various disease contexts. By contrast, a previous review primarily focused on traditional OSA treatment options, such as CPAP, oral appliances and surgery, without exploring the emerging potential of A2AR agonists (163). In conclusion, the present review stands out for its comprehensive integration of multiple mechanisms, its focus on the interplay between inflammation and metabolism and its exploration of clinical applications and limitations. Compared to earlier reviews, it offers a more detailed and multi-faceted perspective, advancing knowledge in the field of OSA and providing valuable resources for future research and clinical applications.