Serum free fatty acids mediate the association between metal elements and cardiometabolic diseases

Background: Metal-associated free fatty acids (FFAs) on cardiometabolic diseases have rarely been studied. Objective: To investigate metallomics-FFAs relationship, and identify FFAs as potential mediators linking metals to cardiometabolic diseases. Methods: In a nationally representative survey, 18 metals (blood/serum/urine) and 30 serum FFAs were assessed. Weighted linear regression, least absolute shrinkage selection operator, quantile g-computation and receiver operating characteristic were used to analyze associations between metal exposure and FFAs, with mediation and bioinformatics analyses exploring underlying mechanisms. Results: Blood selenium (Se), mercury (Hg), lead (Pb); serum copper (Cu), zinc (Zn); and urinary arsenic (As) were positively correlated with FFAs [effect range: 5.74% (95% CI: 2.71, 8.85) to 33.08% (95% CI: 28.73, 37.58)], whereas urinary tungsten, molybdenum, and cobalt showed negative associations [-6.17% (95% CI: −9.54, −2.68) to −9.68% (95% CI: −13.75, −5.42)]. Metal mixture was positively associated with most FFAs [15.66% (95% CI: 0.11, 33.62) to 60.35% (95% CI: 40.19, 83.42)]. Key contributors to FFAs disturbance include serum Cu/Zn, blood Hg/Pb, and urinary As. FFAs (primarily nervonic acid and docosapentaenoic acid) mediated the associations of blood metals (Pb, Hg, Se) and serum Zn with cardiometabolic markers (proportions: 6.98%–84.71%). Inflammatory pathways (e.g., IL-17, TNF) may link metal-induced FFA dysregulation to lipotoxicity and cardiometabolic risk. Conclusions: Our findings provide exploratory evidence connecting metallomics with FFAs and cardiometabolic diseases, suggesting FFAs as potential biomarkers for metal exposure and cardiometabolic diseases prevention.