Unraveling the molecular mechanisms of PFOA in clear cell renal cell carcinoma through network toxicology and molecular docking strategies.

BACKGROUND

As Perfluorooctanoic Acid (PFOA) has been extensively utilized as a processing aid in the manufacture of non-stick coatings, waterproof materials, and other products, concerns regarding its adverse health effects have emerged. Epidemiological data revealed a strong correlation between renal cell carcinoma (RCC) and PFOA concentration, while animal experimental results also demonstrate the association between PFOA and RCC. However, the key targets and mechanisms underlying PFOA-induced RCC remain elusive. This study utilized network toxicology to elucidate the critical target genes and mechanisms of PFOA-induced clear cell RCC (ccRCC), the most prevalent RCC subtype.

METHODS

We retrieved potential PFOA targets from the Swiss Target Prediction database, ChEMBL, and STITCH, and identified RCC-related targets from GeneCards and OMIM. Transcriptomic data for ccRCC patients were obtained from The Cancer Genome Atlas Program (TCGA) to identify differentially expressed genes. We intersected genes from these datasets for constructing a protein-protein interaction (PPI) network. Hub genes were identified from the network using MCODE and cytoHubba plugins in Cytoscape. A risk score based on these hub genes was developed for prognostic analysis, and molecular docking was applied to validate the interactions between PFOA and hub targets.

RESULTS

Intersection genes from these datasets, yielding 70 potential PFOA-induced ccRCC targets. Network analysis identified 7 hub genes- CYP2C9, CYP3A4, CYP1A1, CYP1A2, CYP2B6, CYP2C8 , and ABCB1 , and molecular docking confirmed PFOA's binding affinity to their corresponding proteins. Enrichment analysis using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome databases on the 70 potential targets and 7 hub genes revealed four potential mechanisms of PFOA-induced ccRCC: abnormal xenobiotic metabolism and accumulation of toxic intermediates, disrupted lipid homeostasis, oxidative stress and reactive oxygen species (ROS) generation, and disrupted steroid hormone signaling.

CONCLUSION

Our findings provide novel insights into PFOA-induced ccRCC mechanisms, with implications for risk assessment and environmental health.