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BACKGROUND: Higher circulating carotenoids are associated with lower breast cancer risk. The underlying biology remains under-explored.METHODS: We profiled 293 prediagnostic plasma metabolites in a nested case-control study ( = 887 cases) within the Nurses' Health Studies. Associations between circulating carotenoids and metabolites were identified using linear-mixed models (FDR ≤ 0.05), and we further selected metabolites most predictive of carotenoids with LASSO. Metabolic signatures for carotenoids were calculated as weighted sums of LASSO selected metabolites. We further evaluated the metabolic signatures in relation to breast cancer risk using conditional logistic-regression.RESULTS: We identified 48 to 110 metabolites associated with plasma levels of α-carotene, β-carotene, β-cryptoxanthin, estimated-vitamin-A-potential, lutein/zeaxanthin, and lycopene, which included primarily positively associated metabolites implicated in immune regulation (tryptophan), redox balance (plasmalogens, glutamine), epigenetic regulations (acetylated-/methylated-metabolites), and primarily inversely associated metabolites involved in β-oxidation (carnitines; FDR ≤ 0.05). The metabolomic signatures derived for β-carotene (Q4 vs. Q1 relative risk RR = 0.74, = 0.02), and estimated-vitamin-A-potential (Q4 vs. Q1 RR = 0.74, = 0.02)-measured ≥10 years before diagnosis-were associated with lower breast cancer risk. Modest attenuations of RR for measured levels of β-carotene and estimated-vitamin-A-potential were seen when we adjusted for their corresponding metabolic signatures.CONCLUSIONS: Metabolites involved in immune regulation, redox balance, membrane signaling, and β-oxidation were associated with plasma carotenoids. Although some metabolites may reflect shared common food sources or compartmental colocalization with carotenoids, others may signal the underlying pathways of carotenoids-associated lowered breast cancer risk.IMPACT: Consumption of carotenoid-rich diet is associated with a wide-range of metabolic changes which may help to reduce breast cancer risk.