ArticleThe EMBO journal2022
Cellular responses to halofuginone reveal a vulnerability of the GCN2 branch of the integrated stress response.
Article in The EMBO journal, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 24 citations in OpenAlex.
- Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles.Molecular therapy. Nucleic acids · 2026Article
- Tuning tRNA synthetase inhibition reveals parabolic induction of stress granules limited in size and RNA content.RNA (New York, N.Y.) · 2026Article
- Halofuginone is a Molecular Glue Degrader of Integrin β4.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- tRNA synthetase activity is required for stress granule and P-body assembly.Genes & development · 2026Article
- Article
- Roles of the integrated stress response in regulation of inflammatory reactions.Frontiers in immunology · 2026Review
- Aminoacyl-tRNA synthetases in tumor immunity: canonical translation, source-resolved immune circuits and therapeutic opportunities.Frontiers in immunology · 2026Review
- Drug repurposing screen identifies an HRI activating compound that promotes adaptive mitochondrial remodeling in MFN2-deficient cells.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Pharmacological targeting of RIG-I can selectively activate the integrated stress response.Science advances · 2025Article
- Traditional medicine meets modern science: Halofuginone's role in combating autoimmune diseases.Journal of natural medicines · 2025Review
- African swine fever virus MGF505-3R facilitates ferroptosis to restrict TBK1-IRF3 pathway.Microbiology spectrum · 2025Article
- Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in MFN2-deficient Cells.bioRxiv : the preprint server for biology · 2025Article
- The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21.Science advances · 2025Article
- New uses of halofuginone to treat cancer.Journal of pharmaceutical analysis · 2025Review
- Integrated stress response activator halofuginone protects mice from diabetes-like phenotypes.The Journal of cell biology · 2024Article
- Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity.Circulation research · 2024Article
- Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells.Cell chemical biology · 2023Article
- Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.International journal of molecular sciences · 2023Review
- Non-Essential Amino Acid Availability Influences Proteostasis and Breast Cancer Cell Survival During Proteotoxic Stress.Molecular cancer research : MCR · 2023Article
- Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells.bioRxiv : the preprint server for biology · 2023Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Halofuginone (HF) is a phase 2 clinical compound that inhibits the glutamyl-prolyl-tRNA synthetase (EPRS) thereby inducing the integrated stress response (ISR). Here, we report that halofuginone indeed triggers the predicted canonical ISR adaptations, consisting of attenuation of protein synthesis and gene expression reprogramming. However, the former is surprisingly atypical and occurs to a similar magnitude in wild-type cells, cells lacking GCN2 and those incapable of phosphorylating eIF2α. Proline supplementation rescues the observed HF-induced changes indicating that they result from inhibition of EPRS. The failure of the GCN2-to-eIF2α pathway to elicit a measurable protective attenuation of translation initiation allows translation elongation defects to prevail upon HF treatment. Exploiting this vulnerability of the ISR, we show that cancer cells with increased proline dependency are more sensitive to halofuginone. This work reveals that the consequences of EPRS inhibition are more complex than anticipated and provides novel insights into ISR signaling, as well as a molecular framework to guide the targeted development of halofuginone as a therapeutic.
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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.