Investigation of Key Molecular Mechanisms of 6PPDQ in Breast Cancer Development and Progression through Network Toxicology and Computational Simulation

Background The rapid expansion of tire manufacturing has led to widespread environmental contamination by 6PPD-quinone (6PPDQ). Although 6PPDQ exhibits well-documented toxicological properties, its mechanistic links to breast cancer pathogenesis remain unexplored. This study represents the first attempt to examine these associations using network toxicology approaches. Methods Putative 6PPDQ targets were retrieved from PharmMapper and SwissTargetPrediction. Breast cancer datasets (GSE3744, GSE15852, GSE21422) from GEO were used for differential expression analysis and diagnostic modeling, with GSE52194 for validation. WGCNA identified disease modules and hub genes; GeneCards curated breast cancer gene sets. Intersection of 6PPDQ targets and hub genes yielded cross-targets for GO/KEGG enrichment and PPI network analysis. Topological algorithms (DMNC, MCC, Degree, EPC) prioritized key cross-targets. Molecular docking validated 6PPDQ-protein binding interactions. Results Thirty-six cross-target genes were successfully identified. Functional enrichment analysis revealed predominant involvement in cholesterol biosynthesis inhibition, hormone metabolic processes, and carboxylic acid binding, alongside significant pathway enrichment in PI3K-Akt signaling, breast cancer-specific cascades, transcriptional misregulation in cancer, AMPK signaling, IL-17 signaling, and xenobiotic metabolism via cytochrome P450. Integration of two machine learning algorithms with four Cytoscape topological approaches multi-dimensionally pinpointed two core genes: ESR1 and HMGCR. The risk prediction model constructed upon these genetic markers demonstrated robust predictive capability. Molecular docking analyses confirmed strong binding affinities between 6PPDQ and both core targets, with calculated binding energies of -7.7 kcal/mol for ESR1 and − 7.9 kcal/mol for HMGCR. Conclusions This investigation establishes ESR1 and HMGCR as pivotal targets mediating 6PPDQ-induced breast carcinogenesis. Our findings suggest that 6PPDQ promotes breast cancer development through multifaceted mechanisms encompassing metabolic reprogramming with cholesterol synthesis suppression, disruption of hormonal homeostasis, tumor microenvironment modulation, and activation of oncogenic signaling pathways. These discoveries furnish novel mechanistic insights into 6PPDQ-mediated breast cancer pathogenesis and establish a theoretical foundation for therapeutic target development.