ArticleCancer research2022
GLS2 Is a Tumor Suppressor and a Regulator of Ferroptosis in Hepatocellular Carcinoma.
Article in Cancer research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 108 papers, 1 of them a synthesis that pooled it.
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Who cites it
108 citing papers in PubMed, 1 synthesis or guideline pooled it, 153 citations in OpenAlex.
- Aberrant Energy Metabolism in Tumors and Potential Therapeutic Targets.Genes, chromosomes & cancer · 2024Pooled it
- Inhibition or induction of gastrointestinal tumors by ferroptosis and intervention by herbal extracts (Review).Oncology letters · 2026Review
- Ferroptosis in liver biology and diseases.Hepatology communications · 2026Review
- The Emerging Role of Ferroptosis in Pediatric Cancer Biology and Therapy.International journal of molecular sciences · 2026Review
- Metabolism, autophagy, and cell death: The triangular axis in tumor survival and therapeutic resistance.Redox biology · 2026Review
- Unraveling the role of glutamine metabolism in cancer: from cell death mechanisms to tumor microenvironment modulation.Experimental hematology & oncology · 2026Review
- LSD1-GLS2 axis drives subtype-specific chemoresistance in pancreatic cancer through glutaminolysis reprogramming.Cell death & disease · 2026Article
- Oxidative Stress Induced Senescent Macrophage-Driven Squamous Cell Carcinoma Invasion via Glutamine Metabolic Reprogramming.Aging cell · 2026Article
- Amino Acids as Targets for Immunotherapy against Solid Tumors.Cell biochemistry and biophysics · 2026Review
- Unveiling melatonin's multifaceted actions against ferroptotic neurotoxicity in ischemic stroke.Toxicology reports · 2026Review
- Overview of glutamine metabolism in stromal components of the tumor microenvironment and potential anti-tumor therapies.Genes & diseases · 2026Review
- Hepatocellular carcinoma's inflammatory secret: ferroptosis as the key.Translational cancer research · 2026Article
- Article
- Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.Molecular biomedicine · 2026Review
- Ferroptosis in cardiovascular diseases: molecular mechanisms and a novel therapeutic target.Molecular biomedicine · 2026Review
- Pan-Cancer profiling of ferroptosis-related genes reveals prognostic biomarkers and sex-specific associations.Clinical and translational radiation oncology · 2026Article
- Mitochondrial LINC00942 activates complex I and inhibits ferroptosis through interacting with GRSF1 in liver cancer.Science China. Life sciences · 2026Article
- Interplay between natural killer cells and ferroptosis: novel insights in tumor immunity and therapeutic potential.Cell communication and signaling : CCS · 2026Review
- Article
- The Role of Kupffer Cells and Liver Macrophages in the Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease.Biomedicines · 2026Review
48 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
Glutamine synthase 2 (GLS2) is a key regulator of glutaminolysis and has been previously implicated in activities consistent with tumor suppression. Here we generated Gls2 knockout (KO) mice that develop late-occurring B-cell lymphomas and hepatocellular carcinomas (HCC). Further, Gls2 KO mice subjected to the hepatocarcinogenic Stelic Animal Model (STAM) protocol produce larger HCC tumors than seen in wild-type (WT) mice. GLS2 has been shown to promote ferroptosis, a form of cell death characterized by iron-dependent accumulation of lipid peroxides. In line with this, GLS2 deficiency, either in cells derived from Gls2 KO mice or in human cancer cells depleted of GLS2, conferred significant resistance to ferroptosis. Mechanistically, GLS2, but not GLS1, increased lipid reactive oxygen species (ROS) production by facilitating the conversion of glutamate to α-ketoglutarate (αKG), thereby promoting ferroptosis. Ectopic expression of WT GLS2 in a human hepatic adenocarcinoma xenograft model significantly reduced tumor size; this effect was nullified by either expressing a catalytically inactive form of GLS2 or by blocking ferroptosis. Furthermore, analysis of cancer patient datasets supported a role for GLS2-mediated regulation of ferroptosis in human tumor suppression. These data suggest that GLS2 is a bona fide tumor suppressor and that its ability to favor ferroptosis by regulating glutaminolysis contributes to its tumor suppressive function. SIGNIFICANCE: This study demonstrates that the key regulator of glutaminolysis, GLS2, can limit HCC in vivo by promoting ferroptosis through αKG-dependent lipid ROS, which in turn might lay the foundation for a novel therapeutic approach.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.