Cadmium dominates urinary heavy metal mixtures associated with COPD risk: Integrative evidence from NHANES, network pharmacology, and experimental validation

OBJECTIVE: This study aimed to examine the associations between heavy metal exposures and the prevalence of chronic obstructive pulmonary disease (COPD), identify the principal toxicant, and elucidate the molecular mechanisms underlying its pathogenic effects. METHODS: We analyzed 3380 adults from three National Health and Nutrition Examination Survey (NHANES) cycles. Logistic regression, Bayesian Kernel Machine Regression (BKMR), and Quantile-based G-computation (qgcomp) were applied to evaluate individual and joint associations between urinary concentrations of ten heavy metals (arsenic [As], cadmium [Cd], lead [Pb], cobalt [Co], barium [Ba], cesium [Cs], molybdenum [Mo], antimony [Sb], thallium [Tl], and tungsten [W]) and COPD risk. Network pharmacology and molecular docking were used to identify Cd-related molecular targets and pathways, which were validated by immunofluorescence, and western blotting in a Cd-exposed mouse model. RESULTS: Among 3380 participants (mean age: 46.0 years), 456 (13.5%) had COPD. Cd exposure was significantly associated with increased COPD risk (OR=1.79, 95% CI: 1.51-2.13) and was identified as the predominant contributor. The hub proteins exhibited strong binding affinities to Nuclear Factor κ-Light-Chain Enhancer of Activated B Cells 1 (NFKB1; NF-κB p50) and Hypoxia-Inducible Factor 1 alpha (HIF1A), implicating oxidative stress, inflammation, and cell survival pathways. In vivo, Cd inhalation induced emphysematous and fibrotic changes, elevated matrix metalloproteinase (MMP) expression, and NF-κB activation in mice, consistent with silico predictions. CONCLUSION: Cd exposure was identified as the predominant heavy metal associated with increased odds of COPD. Integrative epidemiological, mechanistic, and experimental evidence implicates Cd-induced oxidative stress, inflammation, and tissue remodeling as key pathogenic processes.