Elucidating the Mechanisms of Trichloroethylene‐Induced Kidney Cancer: Network Toxicology, Molecular Docking, and In Vitro Validation
TL;DR
A mechanistic framework is established demonstrating that TCE promotes kidney carcinogenesis by directly dysregulating TP53, ACTB, and CASP3, offering critical insights into environ‐mental oncogenesis and potential therapeutic interventions.
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.