Combining mendelian randomization analysis and network toxicology strategy to identify causality and underlying mechanisms of environmental pollutants with glioblastoma: A study of Methyl-4-hydroxybenzoate.

in Ecotoxicology and environmental safety by Haimin Song, Huaiyu Zhou, Shaochun Yang, Chunming He

TLDR

  • The study found that an aromatic small molecule called Methyl-4-hydroxybenzoate (MEP) is linked to the development of a type of brain tumor called glioblastoma (GBM). The study used a special method called Mendelian Randomization (MR) to determine the causal relationship between MEP and GBM. The study also identified key targets that could be potential therapeutic targets for GBM. The study suggests that MEP may play a role in the development of GBM by affecting certain pathways in the brain. Future research could focus on validating the identified targets and exploring their role in GBM treatment.

Abstract

An increasing number of environmental pollutants are associated with human diseases. We explored the mechanisms by which an aromatic small molecule -- Methyl-4-hydroxybenzoate (MEP) contribute to the development of glioblastoma (GBM). The causality of MEP and GBM were identified via the Mendelian Randomization (MR) analysis. We identified the key targets by integrating the targets of GBM, differential expressed genes (DEGs) from GEO and target genes of MEP. The network of hub genes was obtained from STRING and Cytoscape tools and GO, KEGG enrichment analysis were conducted by clusterProfiler R package. These hub targets were executed molecular docking via Autodock software. MEP had a causal association with GBM as risk factors (P < 0.05, OR > 1). 46 key targets were derived, in which CASP3, MMP2 and CDK4 were screened as the hub targets. MEP might play a role in the GBM by affecting the pathways of neuroactive ligand-receptor interaction, Molecular docking analysis showed a good binding ability of between MEP and CASP3, MMP2, CDK4, CASP8 and MCL1. A causal relationship between MEP and GBM exists. CASP3, MMP2, CDK4, CASP8 and MCL1 have been identified as the crucial targets correlating with GBM. This discovery may provide an important insight into how environmental pollutants contribute to the development of GBM.

Overview

  • The study explores the mechanisms by which an aromatic small molecule, Methyl-4-hydroxybenzoate (MEP), contributes to the development of glioblastoma (GBM).
  • The causality of MEP and GBM was identified via Mendelian Randomization (MR) analysis. Key targets were identified by integrating the targets of GBM, differential expressed genes (DEGs) from GEO and target genes of MEP. The network of hub genes was obtained from STRING and Cytoscape tools and GO, KEGG enrichment analysis were conducted by clusterProfiler R package. Molecular docking was used to analyze the binding ability of MEP with the identified hub targets. The study found a causal relationship between MEP and GBM, with CASP3, MMP2, CDK4, CASP8 and MCL1 identified as the crucial targets correlating with GBM.

Comparative Analysis & Findings

  • The study identified a causal relationship between MEP and GBM via Mendelian Randomization (MR) analysis. The key targets were identified by integrating the targets of GBM, DEGs from GEO and target genes of MEP. The network of hub genes was obtained from STRING and Cytoscape tools and GO, KEGG enrichment analysis were conducted by clusterProfiler R package. Molecular docking was used to analyze the binding ability of MEP with the identified hub targets. The study found that MEP had a causal association with GBM as risk factors (P < 0.05, OR > 1). The key targets identified were CASP3, MMP2, CDK4, CASP8 and MCL1, which were screened as the hub targets. MEP might play a role in the GBM by affecting the pathways of neuroactive ligand-receptor interaction, Molecular docking analysis showed a good binding ability of between MEP and CASP3, MMP2, CDK4, CASP8 and MCL1.

Implications and Future Directions

  • The study provides an important insight into how environmental pollutants contribute to the development of GBM. The identified key targets, CASP3, MMP2, CDK4, CASP8 and MCL1, have been implicated in GBM pathogenesis and could be potential therapeutic targets. The study's findings suggest that MEP may play a role in the GBM by affecting the pathways of neuroactive ligand-receptor interaction. Future research could focus on validating the identified targets and exploring their role in GBM pathogenesis and treatment. Additionally, the study's findings could be used to develop targeted therapies for GBM, which could improve patient outcomes.
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