Introduction Chronic low-grade inflammation underlies many noncommunicable diseases. Although flavonoids exhibit anti-inflammatory and antioxidant effects, population-level evidence distinguishing subclass and monomer specific associations with systemic inflammation remains limited. Methods We analyzed data from 12 681 U.S. adults. Dietary flavonoid intakes were assessed in relation to the neutrophil-to-lymphocyte ratio (NLR), systemic immune–inflammation index (SII), and systemic inflammation response index (SIRI). Effects were modeled per interquartile-range (IQR) increase in intake with false discovery rate (FDR) control within each outcome. Dose–response patterns were evaluated using restricted cubic splines, and heterogeneity in the cyanidin and SII association was assessed in prespecified subgroups. Mechanistic hypotheses were explored using network pharmacology and molecular docking. Results In fully adjusted models, higher anthocyanidin intake was associated with lower SII and SIRI but did not remain significant after FDR correction. At the monomer level, peonidin and cyanidin were inversely associated with SII (peonidin: β = −0.73, 95% CI: −1.14 to −0.32, FDR q = 0.023; cyanidin: β = −1.24, 95% CI: −2.07 to −0.41, FDR q = 0.049). Peonidin was inversely associated with SIRI (β = −0.00192, 95% CI: −0.00275 to −0.00110, FDR q = 0.007). Only cyanidin showed consistent associations across primary and spline analyses in SII. The cyanidin–SII association varied by education and by histories of stroke and chronic obstructive pulmonary disease (COPD), with stronger inverse associations among participants with at least a high-school education, without prior stroke, and with COPD. Network pharmacology identified 334 putative cyanidin–inflammation targets and highlighted hub nodes including epidermal growth factor receptor (EGFR), HSP90AA1, AKT1, SRC, PIK3R1, GRB2. Conclusion In this cross-sectional study, higher anthocyanidin intake, particularly cyanidin, was associated with lower SII, and in silico analyses prioritized reactive oxygen species and kinase signaling pathways as testable mechanisms. Prospective studies and experimental validation are needed to establish temporal direction and causality.
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