Integrating biochemical and computational approaches to identify targeted therapeutic strategies for liver fibrosis: Effects of Telaglenastat (CB-839) on the glutaminase pathway.

PURPOSE: Liver fibrosis, which can progress to liver cirrhosis and hepatocellular carcinoma, presents a significant health challenge. This study evaluates the effects of two l-glutaminase (GLS) inhibitors, Telaglenastat (CB-839) and compound 968, on carbon tetrachloride (CCl4)-induced liver fibrosis in rats.

METHODS

Sixty rats were divided into six groups: control, CB-839, 968, CCl4, CCl4+CB-839, and CCl4+968. Liver tissues were analyzed for fibrosis biomarkers, including l-hydroxyproline, GLS levels, and gene expression of transforming growth factor beta-1 (TGF-β1), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), peroxisome proliferator-activated receptor gamma (PPAR-γ), GLS-1, GLS-2, and sodium-dependent neutral amino acid transporter-2 (SNAT-2).

RESULTS

CCl4 treatment caused significant liver damage, indicated by elevated liver enzymes and hydroxyproline levels. CB-839 significantly reduced these markers, suggesting a protective effect against fibrosis. In contrast, 968 had minimal effects on liver enzymes and hydroxyproline. Gene expression analysis revealed that CCl4 increased fibrotic markers while decreasing PPAR-γ expression. CB-839 downregulated SNAT-2 and TGF-β1, likely by inhibiting glutamine metabolism. Histopathological assessments confirmed reduced collagen deposition with CB-839 treatment. Network pharmacology identified 115 potential targets for CB-839, with notable overlap in liver fibrosis pathways, suggesting its potential as an antifibrotic agent and a foundation for future therapies.

CONCLUSION

These findings demonstrate that CB-839 exhibits significant antifibrotic effects in a rat model of liver fibrosis, primarily by modulating glutamine metabolism and key fibrotic biomarkers. CB-839 has the potential to be a promising therapeutic approach for liver fibrosis.