Serum Copper-to-Zinc Ratio and Oxidative Stress Are Associated with Anemia in Older Adults with Cardiovascular–Kidney–Metabolic Syndrome

: Chronic oxidative stress is a molecular hallmark of cardiovascular-kidney-metabolic (CKM) syndrome, yet its contribution to CKM-associated anemia beyond erythropoietin deficiency and iron restriction is poorly characterized. The serum copper-to-zinc (Cu/Zn) ratio reflects impaired Cu/Zn-SOD1 antioxidant capacity and inflammatory trace-element imbalance, but its relationships with circulating redox biomarkers and its hematological relevance in CKM syndrome has never been explored in a community-dwelling cohort of older adults. We analyzed 2391 NHANES 2011-2016 participants ≥ 50 years of age with CKM stage I-IV. To explore whether the serum Cu/Zn ratio was associated with oxidative stress and immunomodulatory biomarkers as well as with the odds of anemia, we used survey-weighted Spearman correlations, linear regression (outcome: hemoglobin), and logistic regression (outcome: anemia); multivariate models were adjusted for a panel of antioxidant or immunomodulatory biomarkers (selenium, vitamin D), pro-oxidant biomarkers (lead, cadmium, cotinine, uric acid), red cell distribution width (RDW) as a composite biomarker of erythrocyte stress, neutrophil-to-lymphocyte ratio (NLR), CKM stage, and comorbidities. The molecular targets of the nine biomarkers were mapped onto a protein-protein interaction network using the STRING database v12.0 to contextualize regression findings within a systems biology framework. Anemia was present in 205 participants (8.6%). The Cu/Zn ratio was inversely correlated with the antioxidant marker selenium (r = -0.19; p < 0.001) and positively correlated with the pro-oxidant markers RDW (r = +0.21; p < 0.001) and cadmium (r = +0.10; p < 0.001), consistent with its role as a hub within the CKM redox network. In fully adjusted models, a higher Cu/Zn ratio was independently associated with prevalent anemia (OR = 2.94; 95% CI: 1.61-5.37) and lower hemoglobin (β = -0.55 g/dL); among included biomarkers, selenium and cadmium were independently protective (OR = 0.76 per 10 µg/L and 0.23 per µg/dL, respectively), and RDW and uric acid were independently harmful (OR = 2.20 per 1% and 1.33 per mg/dL, respectively). The Cu/Zn ratio correlated with both antioxidant depletion and pro-oxidant accumulation in CKM syndrome and was independently associated with anemia within this oxidative network. Together with selenium, cadmium, RDW, and uric acid, it defines an oxidative stress-driven hematological pathway that may contribute to the development and progression of anemia in patients with CKM syndrome.