Citrate-modified
silver nanoparticles (AgNP-
cit) have received extensive attention due to their excellent antimicrobial properties. However, these particles tend to migrate in vivo, thereby entering the blood circulatory system in granular form and accumulating in the liver, causing toxic reactions. However, the mechanism underlying AgNP-
cit toxicity is not yet clear. Thus, we adopted a tandem mass tag (TMT)-labeled quantitative proteomics and metabolomics approach to identify
proteins and small molecule metabolites associated with AgNP-
cit-induced liver damage and constructed interaction networks between the differentially expressed
proteins and metabolites to explain the AgNP-
cit toxicity mechanism. AgNP-
cit resulted in abnormal
purine metabolism mainly by affecting
xanthine and other key metabolites along with
pyruvate kinase and other bodily
proteins, leading to oxidative stress. AgNP-
cit regulated the metabolism of
amino acids and
glycerol phospholipids through
glycerol phospholipids, CYP450
enzymes and other key
proteins, causing liver
inflammation. Via
alanine,
isoleucine,
L-serine dehydratase/
L-threonine deaminase and other
proteins, AgNP-
cit altered the metabolism of
glycine,
serine and
threonine,
cysteine and
methionine, affecting oxidation and deamination, and ultimately leading to liver damage. This work clearly explains toxic reactions induced by AgNP-
cit from three perspectives, oxidative stress, inflammatory response, and oxidation and deamination, thus providing an experimental basis for the safe application of nanomaterials.