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

Objective: This study aimed to investigate the associations between urinary concentrations of multiple heavy metals (HMs) and the prevalence of chronic obstructive pulmonary disease (COPD) in a representative U.S. population, identify the principal toxic metal, and elucidate potential molecular mechanisms underlying its pathogenic effects. Methods: A total of 3,380 adults aged ≥20 years from three NHANES cycles (2007–2012) were included. Logistic regression and restricted cubic spline (RCS) models were used to evaluate associations between individual urinary HMs and COPD risk. Mixture effects were analyzed using Bayesian kernel machine regression (BKMR) and quantile-based g-computation (qgcomp). Network pharmacology and molecular docking were applied to identify molecular targets and signaling pathways associated with COPD, which were further validated through immunohistochemistry, immunofluorescence, and Western blotting in a Cd-exposed mouse model. Results: Among 3,380 participants (mean age 46.0 ± 16.1 years; 49.6% males), 456 (13.5%) had COPD. Co-exposure to urinary HMs was associated with elevated COPD risk (OR = 1.65; 95% CI: 1.30–2.08), with cadmium (Cd) identified as the major contributor (weight = 0.63). BKMR analysis confirmed Cd as the top-ranked metal (PIP = 1.00), showing a clear positive dose–response relationship. Network pharmacology and molecular docking revealed ten hub proteins potentially mediating Cd’s effects, with strong binding affinities to NFκB1 and HIF1A. Functional enrichment indicated involvement of oxidative stress, inflammation, and cell survival pathways. Cd inhalation in mice induced emphysematous and fibrotic changes, elevated MMP expression, and NF-κB activation, consistent with in silico predictions. Conclusions: Our findings provide convergent epidemiological and mechanistic evidence linking urinary Cd exposure to COPD. Cd appears to promote pulmonary injury through NF-κB–centered oxidative and inflammatory signaling. These results highlight Cd as a key environmental risk factor and potential therapeutic target, underscoring the need for stringent regulation of airborne and occupational Cd exposure to mitigate COPD burden.