Targeting Glutamine Metabolismm: A Novel Approach to Combat Hepatic Fibrosis

Fakher, Hoda elsayed; Al-Ashmawy, Ghada Mohamed; Mehanna, Eman taha; Mesbah, Noha; Abo-Elmatty, Dina

doi:10.21608/rpbs.2025.358653.1355

	Targeting Glutamine Metabolismm: A Novel Approach to Combat Hepatic Fibrosis
Records of Pharmaceutical and Biomedical Sciences
Volume 9, Issue 1, March 2025, Page 19-30 PDF (798.6 K)
Document Type: Mini-reviews
DOI: 10.21608/rpbs.2025.358653.1355
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Authors
Hoda elsayed Fakher ¹; Ghada Mohamed Al-Ashmawy²; Eman taha Mehanna³; Noha Mesbah ⁴; Dina Abo-Elmatty⁴
¹Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia , Egypt.
²Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
³Biochemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt.
⁴Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
Abstract
Liver disease causes around 2 million deaths globally each year, with half due to fibrosis and half due to viral hepatitis and hepatocellular carcinoma. Fibrosis ranks as the 11th leading cause of death worldwide. Egypt has the highest prevalence of hepatitis C virus (HCV) infection, impacting 15%-25% of its rural population. Liver fibrosis results from excessive extracellular matrix protein accumulation, primarily collagen, driven by activated hepatic stellate cells (HSCs). These cells transform into fibrogenic myofibroblast-like cells following liver injury. Emerging antifibrotic therapies aim to reduce fibrogenic cell accumulation and extracellular matrix deposition. Glutaminase (GLS) is an enzyme that converts glutamine, the most abundant amino acid in circulation, into glutamate, releasing ammonia. Humans have four GLS isoforms, with GLS-1 and GLS-2 being significant. Glutamine metabolism influences HSC proliferation and activation, with glutamine converting to α-ketoglutarate for the Krebs cycle and pyrroline-5-carboxylate, which stimulates collagen production. In healthy livers, GLS-2 predominates, while in fibrotic livers, GLS-2 levels decrease, and GLS-1 increases in stromal cells. Inhibiting GLS-1 may reduce HSC proliferation and fibrosis. The selective GLS-1 inhibitor CB-839 is in clinical trials, and the small molecule 968 inhibits GLS-2. These inhibitors help elucidate the roles of GLS isoforms and offer new strategies for targeting glutamine metabolism in liver fibrosis.
Keywords
Hepatic fibrosis; GLS; CB-839; 968-compound; TGF-β1


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