ArticleCell metabolism2022
GCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment.
Article in Cell metabolism, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 108 papers, 2 of them syntheses that pooled it.
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Who cites it
108 citing papers in PubMed, 2 syntheses or guidelines pooled it, 138 citations in OpenAlex.
- MicroRNAs and Cellular Senescence in Melanoma: An Underexplored Link to Tumor Progression-A Systematic Review with Bioinformatics Analyses.International journal of molecular sciences · 2026Pooled it
- NFKB1 as a key player in Tumor biology: from mechanisms to therapeutic implications.Cell biology and toxicology · 2025Pooled it
- Balancing essential amino acids in low-protein diets: Impacts on growth performance, amino acid transport, and cecal microbiota in yellow-feathered chickens.Poultry science · 2026Article
- GCN2 in proteostasis: structural logic, signalling networks and disease.The FEBS journal · 2026Review
- Review
- L-2-Hydroxyglutarate sensitizes ferroptosis through ATF3/CHAC1-mediated glutathione degradation in hepatocellular carcinoma.Cell death & disease · 2026Article
- Cellular Senescence and Aging: Mechanisms, Disease Convergence, and Therapeutic Frontiers.MedComm · 2026Review
- Extracellular vesicles derived by hypoxic preconditioned EPCs attenuated atherosclerosis by suppressing ferroptosis via regulating arginine metabolism.Redox biology · 2026Article
- Research progress and therapeutic strategies in hepatocellular carcinoma metabolic reprogramming.Journal of advanced research · 2026Review
- A Novel Potent and Selective GCN2 Inhibitor, APL-4098, Has Antileukemic Activity through Dysregulation of Mitochondrial Function.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Locoregional lactate dehydrogenase inhibition potentiates therapy and overcomes treatment resistance in hepatocellular carcinoma.Hepatology (Baltimore, Md.) · 2026Article
- RNA helicase SKIV2L impedes tumor immunity by reprogramming arginine metabolism of hepatocellular carcinomas.Journal for immunotherapy of cancer · 2026Article
- Arginine dependency in omental metastasis of epithelial ovarian cancer reveals a therapeutic vulnerability.Cell death & disease · 2026Article
- Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.Molecular biomedicine · 2026Review
- Article
- Impaired nitrogenous waste clearance promotes hepatocellular carcinoma.Science advances · 2026Article
- Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review).International journal of molecular medicine · 2026Review
- Decoding amino acid metabolism in hepatocellular carcinoma: critical nodes and novel therapeutic strategy.Frontiers in oncology · 2026Review
- Amino Acid Metabolism in Chronic Liver Disease: from Pathogenic Driver to Therapeutic Target.International journal of biological sciences · 2026Review
- Metabolic Reprogramming-Targeted Therapeutic Strategies in Primary Liver Cancer: A Bibliometric and Visualized Analysis.Journal of hepatocellular carcinoma · 2026Article
48 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Hepatocellular carcinoma (HCC) is a typically fatal malignancy exhibiting genetic heterogeneity and limited therapy responses. We demonstrate here that HCCs consistently repress urea cycle gene expression and thereby become auxotrophic for exogenous arginine. Surprisingly, arginine import is uniquely dependent on the cationic amino acid transporter SLC7A1, whose inhibition slows HCC cell growth in vitro and in vivo. Moreover, arginine deprivation engages an integrated stress response that promotes HCC cell-cycle arrest and quiescence, dependent on the general control nonderepressible 2 (GCN2) kinase. Inhibiting GCN2 in arginine-deprived HCC cells promotes a senescent phenotype instead, rendering these cells vulnerable to senolytic compounds. Preclinical models confirm that combined dietary arginine deprivation, GCN2 inhibition, and senotherapy promote HCC cell apoptosis and tumor regression. These data suggest novel strategies to treat human liver cancers through targeting SLC7A1 and/or a combination of arginine restriction, inhibition of GCN2, and senolytic agents.
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Registered trials
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.