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Integrative network toxicology and molecular docking reveal 4-Nonylphenol's multifaceted mechanisms in breast cancer
1Department of Plastic Surgery, Plastic Surgery Hospital of Shandong Second Medical University, Weifang, Shandong, China.
Objective:
This study employs integrated network toxicology and molecular docking to investigate the molecular basis underlying 4-nonylphenol (4-NP)-mediated enhancement of breast cancer susceptibility.
Methods:
We integrated data from multiple databases, including ChEMBL, STITCH, Swiss Target Prediction, GeneCards, OMIM and TTD. Core compound-disease-associated target genes were identified through Protein-Protein Interaction (PPI) network analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were subsequently employed to elucidate the potential molecular functions and biological pathways associated with these key targets. Molecular docking using AutoDock Vina was conducted to investigate the binding interactions between the core genes and 4-NP. Furthermore, the miRDB database was utilized to identify potential microRNAs (miRNAs) that may exert regulatory control over the pivotal genes.
Results:
Five hub breast cancer target genes associated with 4-NP exposure were screened, containing TP53, HDAC1, ESR1, CTNNB1 and MYC. GO and KEGG analyses revealed that intersecting genes mainly influenced PI3K-Akt signaling, MicroRNAs in cancer, Chemical carcinogenesis-receptor activation and MAPK signaling. Molecular docking confirmed strong binding affinities of 4-NP to these hub genes. Subsequently several high-confidence candidate regulatory miRNAs especially miR-22, -148a, -181a and -152 were identified that shed light on miRNA regulatory mechanisms by which 4-NP increases breast cancer risk.
Conclusion:
Our study demonstrates that 4-NP exposure perturbs protein conformational of hub targets, activating cascades and dysregulating signaling pathway to potentiate breast cancer risk. Furthermore, we identify a novel miRNA-mediated regulatory axis alongside MAPK signaling as critical mechanisms underpinning 4-NP toxicity.
Insights
This study reveals how 4-nonylphenol (4-NP) increases breast cancer risk by altering key genes and signaling pathways. It identifies specific microRNAs (miRNAs) involved in this process, offering new insights into 4-NP toxicity.
Area of Science:
- Environmental toxicology
- Molecular biology
- Cancer research
Background:
- 4-nonylphenol (4-NP) is an environmental endocrine disruptor.
- Increased breast cancer susceptibility has been linked to environmental exposures.
- Understanding the molecular mechanisms of 4-NP toxicity is crucial for public health.
Purpose of the Study:
- To investigate the molecular basis of 4-nonylphenol (4-NP)-enhanced breast cancer susceptibility.
- To identify key genes, pathways, and regulatory elements involved in 4-NP-induced breast cancer risk.
Main Methods:
- Integrated network toxicology and molecular docking approaches.
- Utilized databases like ChEMBL, STITCH, and GeneCards for target identification.
- Performed Protein-Protein Interaction (PPI) network analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses.
- Conducted molecular docking with AutoDock Vina and identified regulatory microRNAs (miRNAs) using miRDB.
Main Results:
- Identified five hub genes (TP53, HDAC1, ESR1, CTNNB1, MYC) associated with 4-NP exposure and breast cancer.
- Enrichment analyses indicated involvement of PI3K-Akt signaling, microRNAs in cancer, chemical carcinogenesis, and MAPK signaling pathways.
- Molecular docking confirmed strong binding of 4-NP to hub genes.
- Identified candidate miRNAs (miR-22, -148a, -181a, -152) potentially mediating 4-NP's effect on breast cancer risk.
Conclusions:
- 4-NP exposure disrupts protein targets, activates signaling cascades, and dysregulates pathways, potentiating breast cancer risk.
- A novel miRNA-mediated regulatory axis and MAPK signaling are identified as critical mechanisms in 4-NP toxicity.
- This study provides a molecular understanding of how environmental chemicals can influence cancer susceptibility.
