Atorvastatin modulates oncogenic and protective transcriptomic signatures in hexachlorobenzene-induced preneoplastic liver lesions in rats

Methods

Male Wistar rats weighing 160 g b.w. were randomly assigned to four experimental groups ( n= 5 per group) : control, HCB (100 mg/kg b.w.), AT (5 mg/kg b.w.), and AT + HCB, treated for 30 days. The analysed parameters were liver weight, body weight, hepatosomatic index, liver histology, and expression levels of target proteins, c-Myc, TGF-β1, and p53 by immunofluorescence (n = 3 per group). Transcriptomic analysis was performed by RNA sequencing on liver tissue (n = 2 per group).

Differentially expressed genes (DEGs) were identified using DESeq2 (|log2FC| > 1, adjusted p < 0.05).. Gene set enrichment analysis (GSEA) and KEGG pathway overrepresentation analysis were conducted using the WebGestalt platform . Results: HCB treatment significantly increased the hepatosomatic index (28%, p<0.01) and induced preneoplastic hepatic lesions, both effects were prevented by AT co-administration.

Transcriptomic analysis of HCB-treated livers identified 6,396 DEGs, of which 1,352 overlapped with the 1,612-gene KEGG “Pathway in cancer” set (83.9% concordance; p = 5.19×10⁻⁵⁴, FDR = 1.82×10⁻⁵¹). HCB activated multiple oncogenic pathways, including RHO GTPase cycle, TGF-β signalling, and receptor tyrosine kinase signalling, AT co-treatment downregulated these HCB-induced pathways and upregulated protective PPAR signalling, autophagy, and cellular stress response pathways.

Consistent with these transcriptomic findings, AT co-administration reduced TGF-β1 and c-Myc protein levels and attenuated the HCB-induced accumulation of total p53 protein levels observed in liver tissue. Conclusions: In this experimental model, Atorvastatin exerted a protective effect against HCB-induced preneoplastic hepatic changes through the modulation of oncogenic and cytoprotective transcriptomic programmes. These findings provide mechanistic insights into statin-mediated hepatoprotection and support further investigation of AT as a potential chemopreventive agent in high-risk populations.

However, additional validation in models that better reflect the chronic liver injury context of human HCC is needed.