Hexachlorobutadiene exposure promotes hepatocellular carcinoma progression via CD8+ T dysfunction and VDR-mediated PI3K/AKT activation: An integrated multi-omics and experimental study
Multi-omics and experimental study reveals that hexachlorobutadiene accelerates liver cancer progression by exhausting CD8+ T cells and activating VDR-PI3K/AKT signaling, highlighting...
Key Points
To investigate the toxicological effects and molecular mechanisms through which hexachlorobutadiene (HCBD) promotes the progression of hepatocellular carcinoma.
Integrated network toxicology with single-cell transcriptomics and flow cytometry to evaluate HCBD-induced CD8⁺ T cell exhaustion markers (PD-1, TIM-3, and TIGIT).
Conducted Mendelian randomization, Bayesian colocalization, and molecular dynamics simulations to identify and validate causal target genes mediating cancer risk.
Performed functional in vitro assays using VDR knockdown and pharmacological PI3K inhibition to assess liver cancer proliferation, migration, and invasion.
Network toxicology identified 139 shared targets between HCBD and liver cancer, with single-cell and flow cytometric validation demonstrating driven differentiation toward an exhausted CD8⁺ T cell phenotype.
Mendelian randomization and docking simulations identified VDR as a direct binding target causally associated with increased hepatocellular carcinoma risk.
HCBD exposure upregulated VDR, transcriptionally activated IGF1, and stimulated downstream PI3K/AKT signaling, significantly enhancing malignant phenotypes in a manner reversible by VDR or PI3K suppression.