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The recent standardization of diagnostic criteria and phenotyping for cardiovascular-kidney-metabolic (CKM) syndrome has increased attention to this multisystem disorder which arises from the interactions among metabolic dysfunction, chronic kidney disease, and cardiovascular disease. The food inflammation index (FII) quantifies diet-induced inflammation and evaluates individuals' susceptibility to inflammatory-mediated health outcomes. However, the mechanisms linking FII derived dietary inflammation to CKM syndrome progression, especially the triglyceride-glucose (TyG) index's mediating role, remain unclear. This study aimed to investigate the association between FII and advanced CKM syndrome and evaluate the mediating role of TyG index. This study used a two-phase design to determine the dose-response relationship between FII and advanced CKM syndrome (stages 3 or 4) and to assess the TyG index's contribution in this link through mediation analysis. Data obtained from the 1999 to 2018 surveys were analyzed, and 20,151 participants were included in the analysis. CKM syndrome staging was done per established criteria, with advanced CKM as stage 3 or 4. Multivariate weighted logistic regression evaluated the association between FII and advanced CKM syndrome, with the TyG index as a mediator. The prevalence of advanced CKM syndrome was 17.37%. FII was significantly associated with advanced CKM stages (odds ratio = 1.03, 95% confidence interval = 1.01-1.04, P < .001), and this association was partially mediated by the TyG index (proportion mediated = 12.52%, 95% confidence interval = 7.25%-25.48%, P < .001). Higher FII levels were associated with an increased risk of advanced CKM syndrome, suggesting that FII may serve as a useful marker for prevention and early detection. The TyG index partially mediated the relationship between FII and advanced CKM syndrome. Future longitudinal studies are warranted to confirm these findings and explore potential interventions targeting dietary inflammation.