Journal Article

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

Lu, Jingying, Tan, Xuemei, Hou, Zhouhua, Shi, Xueting, Zhang, Min, Shi, Shuo

2026

Overview

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.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Algorithms / Animals / Anopheles / Apoptosis - drug effects / Chemical and Drug Induced Liver Injury - etiology / Chemical and Drug Induced Liver Injury - genetics / Chemical and Drug Induced Liver Injury - metabolism / Chemical and Drug Induced Liver Injury - pathology / Connectivity / Genes / Homeostasis / Humans / Inflammation / Kinases / Lipids / Liver / Liver - drug effects / Liver - metabolism / Liver - pathology / Metabolism / Microplastics - chemistry / Microplastics - toxicity / Molecular Docking Simulation / Oxidative stress / Oxidative Stress - drug effects / Phosphatidylinositol 3-Kinases - metabolism / Plastic pollution / Political aspects / Polyethylene terephthalate / Polyethylene Terephthalates - chemistry / Polyethylene Terephthalates - toxicity / Protein Interaction Maps - drug effects / Proteins / Proto-Oncogene Proteins c-akt - metabolism / Signal transduction / Signal Transduction - drug effects / Toxicity / Toxicology