Cobalt mediates stage-specific toxicity of metal mixtures in cardiovascular-kidney-metabolic syndrome.

Cardiovascular-Kidney-Metabolic (CKM) syndrome imposes a rising global health burden, yet the link between environmental metal mixtures and CKM progression remains unclear. To assess the joint effects of metal mixtures on CKM syndrome staging and identify critical toxic drivers through advanced mixture analysis. National Health and Nutrition Examination Survey data (2011 to 2016) from 1,816 participants were analyzed via Weighted Quantile Sum (WQS) regression, generalized linear models (GLMs), ridge regression, Shapley Additive exPlanations (SHAP) analysis, and polynomial regression. An adverse outcome pathway (AOP) framework was utilized to characterize the mechanisms of metal-mediated CKM. The WQS model revealed an association between mixed metal exposure and CKM (β = 0.502, P = 0.013). Subsequently, GLMs and ridge regression further identified the associative characteristics of individual metals, with all 3 models pointing to cobalt as the key driver. The SHAP model validated cobalt's dominant contribution from the perspective of marginal feature importance. Additionally, a polynomial equation analysis showed that cobalt exhibited a linear dose-response relationship with CKM syndrome. Based on these findings, the AOP framework further identified that early CKM stages are linked with cobalt-related metabolic and immune dysregulation. In contrast, late stages involve disruptions in calcium homeostasis, lipid metabolism, and cell apoptosis-survival balance. Our findings highlight the impact of metal exposure on the progression of CKM syndrome; the AOP framework has deciphered stage-specific mechanisms of cobalt, revealing distinct toxicological pathways in early versus late CKM.