Integrative analysis of cadmium exposure and osteoarthritis: from population evidence to molecular mechanisms

This study integrates epidemiological analysis and computational toxicology approaches to systematically investigate the association between cadmium (Cd) exposure and osteoarthritis (OA), as well as the underlying molecular mechanisms. Based on the data from the 2013-2018 National Health and Nutrition Examination Survey (NHANES), multivariate logistic regression models and forest plot analyses revealed that elevated blood cadmium levels were significantly associated with an increased risk of OA, with particularly pronounced effects observed among individuals with diabetes, hypertension, vitamin D deficiency, low income, and smokers. Further, potential cadmium-related targets were identified through network toxicology, and by integrating differentially expressed genes (DEGs) in OA, weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) networks (STRING), a total of 113 intersection genes were obtained. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that cadmium may promote OA progression by regulating pathways, such as cellular senescence, FOXO signaling, and TNF signaling. Through Cytoscape MCC algorithm, forest plot, and Lasso regression analysis, six key hub genes-MYC, FOXO1, FOXO3, ZFP36, AIF1, and KLF4-were identified. Molecular docking simulations further validated the strong binding affinity between cadmium nitrate and these core targets. Overall, this study comprehensively delineates the molecular network by which cadmium exposure may contribute to OA, providing novel insights into the environmental heavy metal toxicity mechanisms and potential therapeutic interventions.