Abstract

Polyethylene terephthalate microplastics (PET-MPs) pose significant environmental and health concerns due to their persistence and potential toxicity, yet their impact on intervertebral disc degeneration (IDD) remains poorly understood. This study integrated network toxicology, machine learning, molecular docking, single-cell transcriptomics, and in vitro experiments to systematically explore the potential mechanisms through which PET-MPs may contribute to IDD. Through combined multi-database screening, WGCNA, and machine learning-based SHAP analysis, five core targets were identified: ANGPTL4, CDC42, CTSK, VKORC1, and FN1. GO and KEGG pathway analyses, complemented by molecular docking and dynamics simulations, revealed significant enrichment in AGE-RAGE, Toll-like receptor, and ECM-related pathways and suggested stable binding of PET with ANGPTL4 and VKORC1. Single-cell transcriptomics demonstrated specific upregulation of these genes in degenerative nucleus pulposus cells, accompanied by enhanced immune–stromal communication. In vitro, PET-MPs dose-dependently induced cytotoxicity, reactive oxygen species overproduction, ECM degradation, and upregulation of Angptl4 and Vkorc1, collectively suggesting a potential pro-degenerative effect on nucleus pulposus cells.