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Article Abstract
N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPDQ), as a recently identified environmental toxicant, has garnered significant attention because of its widespread detection in ecosystems and human habitats. Emerging evidence highlights its potential detrimental effects on various organs. However, its carcinogenic potential remains poorly understood, particularly its role in clear cell renal cell carcinoma (ccRCC). This study seeks to elucidate the molecular mechanisms underlying 6PPDQ exposure and its potential contribution to ccRCC. Potential targets of 6PPDQ (1713) were predicted using PharmMapper, SwissTargetPrediction, SEA, and CTD databases. Integration with Genecard and GEO datasets (GSE53757) identified 2074 ccRCC-related genes and 3161 differentially expressed genes, yielding 70 overlapping targets. GO and KEGG enrichment analyses revealed significant associations with PI3K-AKT, JAK-STAT, and FoxO signaling pathways. PPI network constructed via STRING and analyzed with MCODE identified five hub genes (LGALS3, IL10, MMP9, LCN2, ALB), all with AUC values >0.7 in ROC analysis, indicating diagnostic potential. Single-gene GSEA suggested hub genes modulate ccRCC progression via IL6-JAK-STAT3 and PI3K-AKT-mTOR pathways. Immune infiltration analysis showed significant dysregulation of 20 immune cell types in ccRCC, with strong correlations between hub genes and immune cell infiltration levels. Molecular docking demonstrated good binding affinities (Vina score ≤ -5.0) between 6PPDQ and hub proteins. In 769-P human ccRCC cells treated with 1-2 μM 6PPDQ for 24 h, qPCR confirmed significant upregulation of all five hub genes (*p < 0.05). Through this research, we elucidated the relationship between 6PPDQ and ccRCC in specific important genes and signaling pathways, providing a basic platform for future research on the influence of 6PPDQ on ccRCC.
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