Hepatotoxic Mechanisms of Polyethylene Terephthalate Microplastics Revealed by Network Toxicology, Molecular Docking, and In Vivo Validation

Polyethylene terephthalate microplastics (PET-MPs) are emerging environmental pollutants, but the molecular mechanisms underlying their hepatotoxicity remain poorly understood. Here, we combined network toxicology with experimental validation to investigate how PET-MPs induce liver injury. In silico, we investigated the PET-repeating unit as the molecular basis for target interactions. We identified 59 overlapping genes between 157 putative PET-MPs targets and 1693 liver injury-associated genes. Protein-protein interaction analysis revealed six hub genes (Akt1, PIK3CA, PIK3CB, PIK3CD, PIK3R1, and Src), all components of the PI3K/Akt signaling pathway. Gene ontology analysis showed that PET-MPs affect cellular stress responses and kinase activities, while pathway enrichment analysis identified PI3K-Akt, Ras, and Reactive Oxygen Species pathways as primary targets. Molecular docking demonstrated strong binding affinity between PET-MPs and these core targets (binding free energies <-5 kcal/mol). In vitro, PET-MPs induced mitochondrial depolarization, oxidative stress, upregulation of TNF-α and IL-6, and decreased p-AKT/Akt ratio, accompanied by increased apoptosis; the apoptotic effect was reversed by the Akt Agonist SC79. In vivo experiments confirmed that Akt activation reduced PET-MP-induced liver injury, evidenced by decreased inflammation, lower serum transaminases, and restored oxidative balance. These protective effects were abolished by PI3K/Akt pathway inhibitors. Our study identifies potential therapeutic targets and strategies for PET-MP-induced liver injury.