<p>To examine inflammatory biomarkers as potential mediators in the association between urinary metal exposure and advanced Cardiovascular-Kidney-Metabolic Syndrome (CKM) risk in US adults, and to evaluate urinary metals' association with risk and their predictive value. Analysis included 6249 NHANES participants. Restricted Cubic Spline (RCS) explored dose–response relationships. Multivariable and piecewise logistic regression assessed associations between specific metals and advanced CKM risk at different exposure levels. Receiver Operating Characteristic (ROC) curves evaluated predictive performance. Mediation analysis tested the role of inflammatory biomarkers. Generalized Weighted Quantile Sum (gWQS) regression and machine learning (ML) models further assessed metal mixture effects and mechanisms. Restricted cubic spline analysis indicated linear associations between all urinary metal levels and advanced CKM risk. Elevated levels of the Multi-Metal Inflammatory Index (MMII), cadmium (Cd), and cobalt (Co) were significantly associated with increased risk of advanced CKM: each 1-unit increase was associated with a 122%, 28%, and 14% higher risk, respectively. This association was significant only at higher exposure levels. ROC analysis showed good predictive performance. Inflammatory biomarkers, including WBC, NENO, SIRI, AISI, MHR, and NHR, mediated the associations between MMII/Cd/Co and advanced CKM risk. gWQS and ML analyses confirmed the adverse associations of MMII, Cd, and Co, ranking their importance as MMII &gt; Cd &gt; Co. Higher levels of MMII, Cd, and Co are significantly associated with increased advanced CKM risk among US adults, with inflammatory biomarkers playing a key mediating role. These findings highlight a notable public health consideration.</p> Graphical abstract <p></p>