Evaluating the Carcinogenic Potential and Molecular Mechanisms of 6PPDQ in the Human Stomach Using Organoids and Bulk Sequencing Data: A Multi-Machine Learning Approach Combined with Computational Simulation

Background: The environmental contaminant 6PPD-quinone (6PPDQ), a tire rubber antioxidant derivative, has emerged as a potential health hazard, yet its association with gastric cancer (GC) remains unexplored. This study investigates the molecular mechanisms underlying 6PPDQ-induced GC using network toxicology. Methods: 6PPDQ targets were retrieved from PharmMapper and SwissTargetPrediction databases. GC-related datasets (GSE33335, GSE19826, GSE63089) were obtained from GEO for differential expression analysis and model construction, with GSE112369 (organoid) for validation. Weighted Gene Co-expression Network Analysis (WGCNA) identified disease modules and hub genes, combined with GeneCards screening. Intersection of 6PPDQ and GC targets yielded 19 cross-targets undergoing GO/KEGG enrichment and Protein-Protein Interaction (PPI) analysis. Machine learning algorithms (LASSO, Random Forest, SVM-RFE) and topological methods (DMNC, MCC, Degree, EPC) identified core targets, validated by molecular docking. Results: The 19 cross-targets were enriched in cell cycle regulation (G2/M transition), chromosomal organization, and kinase activity. KEGG analysis highlighted p53, PI3K-Akt, Ras, MAPK signaling pathways, and cancer metabolism. Multi-dimensional screening identified PLAU, MET, and CDK2 as core targets. The three-gene risk model showed robust predictive performance. Molecular docking confirmed strong 6PPDQ binding affinities: -8.3 kcal/mol (MET), -8.1 kcal/mol (CDK2), and -6.7 kcal/mol (PLAU). Conclusion: PLAU, MET, and CDK2 represent core targets in 6PPDQ-induced GC. 6PPDQ promotes tumorigenesis through metabolic reprogramming, hormone metabolism disruption, tumor microenvironment modulation, and PI3K-AKT-CDK2 axis activation. These findings elucidate 6PPDQ's oncogenic mechanisms and provide therapeutic targets for GC prevention.