Combined Analysis of Network Toxicology and Multiomics Revealed the Potential Mechanism of 6PPDQ-Induced Hepatotoxicity in Mice

6PPDQ, a rubber tire-derived environmental pollutant,
exhibits
significant hepatotoxicity. However, its hepatotoxic mechanisms remain
insufficiently studied and systematically evaluated. This study integrated
network toxicology, transcriptomics, and metabolomics to investigate
its toxicity mechanisms. ADMETlab 3.0 was used to predict physicochemical
properties and multiorgan toxicity. The targets related to 6PPDQ and
liver injury were obtained from public databases, and a protein–protein
interaction (PPI) network was constructed to identify key targets.
Meanwhile, molecular docking was performed to assess 6PPDQ’s
binding affinity to core proteins. Transcriptomics and differential
gene expression analysis were performed on the livers of Kunming mice
exposed to 4 mg/kg 6PPDQ to explore transcriptomic alterations, while
metabolomic profiling identified disrupted metabolic pathways. Network
toxicology results reveal that 6PPDQ primarily induces hepatotoxicity
through apoptosis, inflammation, and lipid metabolic disturbances.
Key targets, including P53, Mapk1, Mapk14, Casp8, Traf6, Ripk1, and Tnf, are identified,
with strong binding affinities suggesting direct interactions. Transcriptomic
and metabolomic analyses further confirms disruptions in TNF, NF-kappa
B, oxidative phosphorylation, autophagy pathways, and glycerolipid
metabolism. Overall, this study provides a comprehensive mechanistic
framework for 6PPDQ-induced liver injury in mice and provides a new
perspective for subsequent studies on the mechanism of 6PPDQ hepatotoxicity.