Screening of core targets for Di(2-ethylhexyl) Phthalate-related gastric cancer based on machine learning, molecular
Shenghao Li1, Qing Peng2,3, Liyuan Hao2,3,4
1Department of Integrated Traditional Chinese and Western Medicine Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Purpose:
Given the existing uncertainties regarding the link between Di(2-ethylhexyl) phthalate (DEHP) exposure and gastric cancer (GC) progression, this study aimed to clarify their association, identify the toxic targets of DEHP, and elucidate the underlying molecular mechanisms.
Methods:
Multiple integrated approaches were employed, including Gene Expression Omnibus (GEO) data analysis, network toxicology, molecular docking, and machine learning. STRING and Cytoscape tools were utilized to identify key targets, while Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the functional enrichment of intersecting targets. Machine learning and SHAP analysis were applied to screen core targets in GC. Molecular docking was performed to evaluate the binding affinity of DEHP toward core targets, and 200 ns molecular dynamics simulations were further conducted for representative complexes to validate their dynamic stability.
Results:
A total of 18 key targets were identified using STRING and Cytoscape. GO and KEGG enrichment analyses demonstrated that these intersecting targets were primarily enriched in the extracellular region, as well as the Calcium signaling pathway and cAMP signaling pathway. Through machine learning analyses, 7 key genes (ADRB2, ESRRG, GRIA4, IL13RA2, NR3C2, PLA2G1B, and SULT2A1) were identified as core targets in GC through machine learning analyses. Molecular docking simulations revealed strong binding specificity between DEHP and the target proteins. Among them, NR3C2 and ADRB2 exhibited relatively high predictive importance in the machine learning models. DEHP showed favorable binding affinity toward these core targets, and molecular dynamics simulations further confirmed that ADRB2-DEHP and NR3C2-DEHP complexes maintained stable conformations throughout the simulation.
Conclusions:
Our findings identified GC associated genes that were computationally predicted as potential targets of DEHP. These results indicated structural compatibility between DEHP and its target proteins but did not prove that DEHP exposure accounts for the gene expression changes in GC.
Insights
This study investigated the link between Di(2-ethylhexyl) phthalate (DEHP) and gastric cancer (GC). Researchers identified potential DEHP targets in GC, revealing structural compatibility but not direct causation.
Area of Science:
- Toxicology and Molecular Biology
- Cancer Research
- Environmental Health
Background:
- Di(2-ethylhexyl) phthalate (DEHP) is an environmental chemical with uncertain links to gastric cancer (GC) progression.
- Understanding DEHP's molecular targets and mechanisms in GC is crucial for risk assessment.
Purpose of the Study:
- To clarify the association between DEHP exposure and gastric cancer (GC).
- To identify DEHP's toxic targets in GC.
- To elucidate the underlying molecular mechanisms of DEHP's action in GC.
Main Methods:
- Integrated bioinformatics approaches including GEO data analysis, network toxicology, and machine learning.
- STRING and Cytoscape for target identification; GO and KEGG for functional enrichment.
- Molecular docking and dynamics simulations to assess DEHP-target interactions.
Main Results:
- 18 key targets were identified, enriched in extracellular regions and signaling pathways (Calcium, cAMP).
- Seven core GC genes (ADRB2, ESRRG, GRIA4, IL13RA2, NR3C2, PLA2G1B, SULT2A1) were identified via machine learning.
- DEHP exhibited strong binding affinity and stable interactions with core targets NR3C2 and ADRB2.
Conclusions:
- GC-associated genes were computationally predicted as potential DEHP targets.
- Structural compatibility between DEHP and target proteins was indicated.
- The study did not establish that DEHP exposure directly causes observed gene expression changes in GC.
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