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Elucidating the Mechanisms of Trichloroethylene-Induced Kidney Cancer: Network Toxicology, Molecular Docking, and In
Abstract:
Trichloroethylene (TCE), a pervasive environmental contaminant, is epidemiologically linked to kidney, but the precise molecular mechanisms underlying this association remain insufficiently elucidated. To decipher the toxicological network, an integrated approach combining network toxicology, molecular docking, and in vitro validation was employed, resulting in the identification of TP53, ACTB, and CASP3 as pivotal hubs from 599 intersecting targets. Functional enrichment analyses implicated these targets in the dysregulation of cellular proliferation and apoptosis, predominantly mediated by the PI3K-Akt signaling cascade, while clinical correlation analysis revealed that their significant overexpression in tumor tissues was associated with advanced pathological staging, unfavorable prognosis, and heightened infiltration of immunosuppressive cell populations, including Tr1 cells, macrophages, and exhausted T cells. Furthermore, potential binding interactions between TCE and these proteins were predicted by molecular docking and subsequently validated by in vitro experiments, wherein TCE exposure dose-dependently upregulated TP53 and ACTB expression while concomitantly reducing cleaved CASP3 levels. Collectively, this study establishes a mechanistic framework demonstrating that TCE promotes kidney carcinogenesis by directly dysregulating TP53, ACTB, and CASP3, offering critical insights into environ-mental oncogenesis and potential therapeutic interventions.
Insights
Trichloroethylene (TCE) exposure is linked to kidney cancer. This study identifies TP53, ACTB, and CASP3 as key targets, revealing TCE's role in kidney carcinogenesis and suggesting new therapeutic avenues.
Area of Science:
- Environmental Health
- Toxicology
- Molecular Biology
Background:
- Trichloroethylene (TCE) is a widespread environmental contaminant associated with kidney cancer.
- The exact molecular mechanisms linking TCE exposure to kidney carcinogenesis are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which TCE contributes to kidney carcinogenesis.
- To identify key molecular targets and pathways involved in TCE-induced kidney toxicity.
Main Methods:
- Network toxicology, molecular docking, and in vitro validation were integrated.
- Functional enrichment and clinical correlation analyses were performed.
- TCE's interaction with identified protein targets was assessed in vitro.
Main Results:
- TP53, ACTB, and CASP3 were identified as pivotal targets among 599 intersecting genes.
- These targets are involved in regulating cellular proliferation and apoptosis via the PI3K-Akt pathway.
- TCE exposure upregulated TP53 and ACTB while decreasing cleaved CASP3, indicating direct molecular interactions.
Conclusions:
- TCE promotes kidney carcinogenesis by directly disrupting the function of TP53, ACTB, and CASP3.
- The findings provide mechanistic insights into environmental oncogenesis and potential therapeutic strategies.
