Integrating network toxicology and in vitro validation to elucidate PET microplastic-induced osteoarthritis...

Area of Science:

• Environmental toxicology
• Molecular biology
• Computational biology

Background:

• Osteoarthritis (OA) is a degenerative joint disease with complex pathogenesis.
• Microplastics, particularly polyethylene terephthalate (PET), are emerging environmental contaminants.
• The molecular mechanisms linking PET microplastics (PET-MP) to OA pathogenesis remain largely unexplored.

Purpose of the Study:

• To elucidate the molecular mechanisms by which PET-MP influence OA pathogenesis.
• To identify key molecular targets and pathways affected by PET-MP exposure in OA.
• To explore potential therapeutic targets and biomarkers for PET-MP-induced OA.

Main Methods:

• Integrated network toxicology, machine learning, and in vitro experimental validation.
• Differential gene expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA) on OA datasets.
• Prediction of PET-MP biological targets using ChEMBL, SwissTargetPrediction, and PharmMapper, followed by machine learning screening and molecular docking.
• In vitro validation in PET-MP-treated chondrocytes using immunofluorescence, qRT-PCR, and Western blot.

Main Results:

• Identified 452 PET-associated targets, establishing 12 core PET-MP-OA genes.
• Functional enrichment analysis implicated NF-κB and IL-17 signaling pathways.
• Prioritized six hub genes (AKR1A1, INSR, KIF11, MMP1, KCNN4, TK1) using machine learning.
• In vitro experiments confirmed the predicted expression patterns of these hub genes in chondrocytes.

Conclusions:

• PET-MP may promote OA progression by disrupting inflammation, oxidative stress, and cartilage degradation pathways.
• The identified hub genes provide novel insights into microplastic toxicology in joint diseases.
• These hub genes represent potential therapeutic targets and biomarkers for PET-MP-induced OA.