Aug 2026· Nature Communications· Vol 17· 0 citations· 52 references
Medicine
TL;DR
It is suggested that air pollution may promote lung cancer partly through metabolic pathways related to inflammatory and oxidative processes, providing key insights into potential mechanisms and targets for prevention.
Abstract
Air pollution is a leading environmental cause of lung cancer, yet the underlying biological pathways remain poorly understood. Identifying circulating biomarkers that capture early molecular responses may clarify how air pollutants contribute to carcinogenesis and help identify individuals at elevated risk. We conduct a prospective nested case-control study within two Cancer Prevention Study cohorts, profiling more than 1100 metabolites in pre-diagnostic plasma samples from 1357 participants. Residential concentrations of six major air pollutants are estimated at the time of blood draw. Here we show that eight circulating metabolites are associated with both air pollution exposure and subsequent lung cancer risk. Four metabolites, including γ-glutamylglutamine, phenylacetylglutamate, N-(2-furoyl)glycine, and 4-vinylguaiacol glucuronide, significantly mediate associations for particulate matter and ozone (adjusted q-value < 0.2). These findings suggest that air pollution may promote lung cancer partly through metabolic pathways related to inflammatory and oxidative processes, providing key insights into potential mechanisms and targets for prevention. Exposure to ambient air pollution is an established risk factor for lung cancer. In here, the authors report multiple metabolic perturbations that may mediate the association between ambient air pollution exposure and lung cancer risk.
Introduction Ambient air pollutants have been increasingly implicated in immune-mediated disorders, yet the metabolic perturbations through which long-term exposure may contribute to rheumatoid arthritis (RA) remain insufficiently characterized. Methods We used data from 403,332 RA-free participants in the UK Biobank cohort to investigate the associations among long-term ambient air pollution exposure, plasma metabolic signatures, and incident RA risk. Participants were followed for a median of 14.01 years. Residential annual average concentrations of PM2.5, PM10, NO2, and NOx were linked to participants' addresses, and a composite air pollution score (APS) was calculated to reflect overall exposure burden. Plasma metabolomics data were used to characterize metabolic perturbations related to each pollutant. A machine learning model was applied to identify air pollutant-associated metabolites and construct corresponding metabolic signatures. We then examined the relationships of air pollutants and derived metabolic signatures with RA risk using Cox proportional hazards models. Generalized propensity score analyses were performed to assess whether the findings persisted after covariate balancing, and mediation analyses were conducted to estimate the contribution of metabolic signatures to the relationship of air pollutants and RA. Results Each standard deviation increase in the PM2.5-, NO2-, NOx-, and APS-related metabolic signatures was associated with elevated RA risk, with hazard ratios of 1.208 (95% CI: 1.180, 1.236), 1.141 (95% CI: 1.109, 1.173), 1.174 (95% CI: 1.148, 1.201), and 1.184 (95% CI: 1.156, 1.212), respectively. Similar estimates were observed in generalized propensity score analyses. Metabolic signatures accounted for 15.7% to 21.1% of the associations between air pollution exposure and RA risk. Conclusion These findings suggest that long-term air pollution exposure is associated with incident RA risk and that systemic metabolic perturbations may represent potential biological pathways underlying this association.
Yang-Chang Zhang, Tian Liang, Yang Pu et al.· Frontiers in Public Health· 0 citations
The complex relationship between air pollution, the human microbiome, and lung cancer within a One Health framework is explored, highlighting the mechanistic links between air pollution-induced microbial dysbiosis and lung carcinogenesis.
Jawad Hussain, Muhammad Noman· Electronic Journal of Medica...· 0 citations
Radon is a radioactive gas and a lung carcinogen, yet lacks established blood biomarkers for long-term exposure. We aimed to identify circulating metabolomic and exposomics signatures correlated with reconstructed radon-222 exposure. Metabolites and chemical exposomes were profiled using liquid and gas chromatography-high-resolution mass spectrometry from plasma (n=80). Batch effects were corrected using ComBat, and network and pathway analyses were performed using xMWAS and MetaboAnalyst, respectively. A total of 124 metabolites were correlated with radon, including 41 positive correlations. The strongest positive and negative associations involved unidentified features. Network analysis identified six communities, five of which were directly related to radon. Fatty acyls were the most represented class, followed by benzene derivatives and hydroxy acids and derivatives. Pathway analysis showed enrichment in linoleate, fatty acid, and amino acid metabolism. Our findings demonstrate that integrating metabolomic and chemical exposomes may help identify sensitive biomarkers for radon exposure. We recommend further studies to investigate these pathways in greater mechanistic detail to understand the health effects of radon.
Vrinda Kalia, A. Rajendrakumar, Rodrigo Cruz-Nieto et al.· Environmental Research· 0 citations
Evidence linking long-term multipollutant exposure with incident pulmonary hypertension (PH) and circulating metabolic profiles is limited. We investigated individual and joint air pollution exposures in relation to incident PH, characterized pollution-related circulating metabolic signatures, and evaluated their potential mediating roles. This prospective cohort included 444,346 participants without PH at baseline who had air pollution exposure estimates and nuclear magnetic resonance metabolomics data. PM2.5, PM10, NO2, and NOx were assessed as individual pollutants and jointly summarized using an air pollution score (APS). Exposure-related metabolic signatures were derived by elastic-net regression, and their associations with incident PH and potential mediating contributions were evaluated using Cox proportional hazards models and mediation analyses. During 13.58 years of median follow-up, 2328 participants developed PH. Higher APS was associated with increased PH risk (hazard ratio [HR] per 1-SD increment, 1.12; 95% confidence interval [CI], 1.08-1.17). Individual pollutants were also positively associated with PH, with HRs ranging from 1.06 to 1.93 per 10-μg/m3 increment. Elastic-net regression yielded 105 metabolites for the APS signature and 52-123 metabolites for pollutant-specific signatures, mainly involving lipoprotein-related measures, fatty acids, and amino acids. These signatures were also associated with incident PH (HRs per 1-SD increment, 1.12-1.24). The overall metabolic signature mediated 11.74% (95% CI, 7.91%-18.95%) of the APS-PH association, whereas pollutant-specific signatures mediated 11.38%-26.00% of the corresponding pollutant-PH associations. Both individual pollutants and the weighted APS were positively associated with incident PH, with circulating metabolic alterations potentially contributing to these associations.
Ling Kuang, Er-La Huang, Bing-Yun Zhang et al.· Ecotoxicology and Environmen...· 0 citations
How BDE47 exposure may influence lung adenocarcinoma and highlights the need for environmental pollutant monitoring, while also offering potential biomarkers for cancer prognosis and treatment is revealed.
Ming-Yu Zhao, Xiao-Rong Wu, Yi-Xin Mao et al.· 3 Biotech· 0 citations
Gaseous air pollution is a major environmental risk factor for atherosclerosis, yet the specific molecular networks linking Gaseous air pollution to atherosclerosis are not fully characterized. This study aimed to elucidate how gaseous pollutants drive atherosclerosis using a multi-level framework integrating network toxicology, nine machine-learning algorithms, bulk and single-cell/spatial transcriptomics, molecular docking, clinical tissue/serum validation, and in vitro pollutant-exposure assays. A conserved RXRA–MMP9–TNF axis was identified as a core molecular network linking pollutant exposure to atherosclerosis. Single-cell and spatial transcriptomics showed broad expression of RXRA (Retinoid X Receptor Alpha) in vascular stromal and endothelial cells and its association with xenobiotic and lipid metabolism, whereas MMP9 (Matrix Metallopeptidase 9) and TNF (Tumor Necrosis Factor) were enriched in macrophages, T cells, and mast cells within plaques, correlating with immune cell infiltration. Multiple pollutants displayed high binding affinity to these proteins. Clinical samples showed upregulation of these targets in atherosclerotic tissue and serum. Toluene exposure in THP-1-derived macrophages significantly increased RXRA, MMP9, and TNF mRNA and protein levels. These findings highlight an immune–metabolic interplay centered on the RXRA–MMP9–TNF axis in Gaseous air pollution-driven atherosclerosis, supporting these molecules as candidate biomarkers for environmental health strategies.
Husileng Hai, Qianhe Wang, Juan Li et al.· International Journal of Mol...· 0 citations
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