Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis
Open accessAbstract
Exchange of extracellular cystine for intracellular glutamate by the antiporter system x c − is implicated in numerous pathologies. Pharmacological agents that inhibit system x c − activity with high potency have long been sought, but have remained elusive. In this study, we report that the small molecule erastin is a potent, selective inhibitor of system x c − . RNA sequencing revealed that inhibition of cystine–glutamate exchange leads to activation of an ER stress response and upregulation of CHAC1 , providing a pharmacodynamic marker for system x c − inhibition. We also found that the clinically approved anti-cancer drug sorafenib, but not other kinase inhibitors, inhibits system x c − function and can trigger ER stress and ferroptosis. In an analysis of hospital records and adverse event reports, we found that patients treated with sorafenib exhibited unique metabolic and phenotypic alterations compared to patients treated with other kinase-inhibiting drugs. Finally, using a genetic approach, we identified new genes dramatically upregulated in cells resistant to ferroptosis.
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Eprenetapopt is the first compound to reach a phase 3 clinical trial where triggering ferroptosis is central to its anticancer efficacy.
“eprenetapopt is the first compound to reach a phase 3 clinical trial where triggering ferroptosis is central to its anticancer efficacy.”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [37]
The Results sections on erastin analogs and sorafenib discuss ferroptosis in cancer cells and potential clinical use, but not eprenetapopt. Searches for eprenetapopt, APR-246, and phase 3 trials found no passage establishing that eprenetapopt reached such a trial or that ferroptosis is central to its anticancer efficacy. The cited paper's copy therefore does not address the attributed claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredErastin triggers ferroptosis by indirectly affecting the catalytic cycle of GPX4 via inhibition of the cystine/glutamate antiporter system xc− and consequent decrease in intracellular cysteine and GSH.
“erastin triggers ferroptosis by (indirectly) affecting the catalytic cycle of GPX4 via a mechanism that involves the inhibition of the cystine/glutamate antiporter system xc− and consequent decrease in intracellular cysteine (which derives from cystine reduction in the cytoplasm) and GSH (which is synthesized from cysteine) [539, 548, 549, 551].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [551]
Inhibitors of the cystine/glutamate transporter xCT deplete intracellular glutathione in cancer cells, resulting in iron-dependent ROS accumulation and ferroptosis.
“Inhibitors of this transporter have been found to deplete intracellular glutathione in cancer cells, resulting in iron-dependent accumulation of ROS and a form of cell death termed ferroptosis (Dixon et al., 2012; Dixon et al., 2014; Yang et al., 2014).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Dixon et al., 2014
Sorafenib inhibits system xc− in a manner similar to erastin.
“Indeed, sorafenib acts as an inhibitor of system xc−, similar to erastin [29].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [29]
Erastin induces ferroptosis through silencing SLC7A11 and enhances iron bioavailability through autophagic/lysosomal degradation of ferritin and NCOA4.
“Erastin induces ferroptosis through silencing SLC7A11 [84] and was recently demonstrated to enhance iron bioavailability through autophagic/lysosomal degradation of ferritin and its cargo receptor NCOA4 [63].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [84]
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Self-citationFerroptosis: Mechanisms and links with diseases
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Self-citationHuman Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death
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Self-citationGlobal survey of cell death mechanisms reveals metabolic regulation of ferroptosis
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Self-citationTargeting Metabolism for Cancer Therapy
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The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity
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RSL3 Drives Ferroptosis Through GPX4 Inactivation and ROS Production in Colorectal Cancer
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HSPB1 as a novel regulator of ferroptotic cancer cell death
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Regulated necrosis: disease relevance and therapeutic opportunities
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Self-citationFrom ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy
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HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells
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Regulation of lipid peroxidation and ferroptosis in diverse species
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Self-citationIdentification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells
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The Role of Ferroptosis in Cancer Development and Treatment Response
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The chemistry and biology of ferroptosis
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Self-citationArtemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells
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NUPR1 is a critical repressor of ferroptosis
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“While other clinical compounds including sorafenib ( 37 ), sulfasala-zine ( 21 ), artemisinin ( 38 ), and statins, as well as conventional chemotherapy, immune checkpoint inhibitors, and radiotherapy ( 39 ), have demonstrated capacity to induce or enhance sensitivity to ferroptosis, eprenetapopt is…”
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- Authors
- Dixon, S. J., Patel, D. N., Welsch, M., Skouta, R., Lee, E. D., Hayano, M., Thomas, A. G., Gleason, C. E., Tatonetti, N. P., Slusher, B. S., & Stockwell, B. R.
- Affiliations
- Columbia University (US)
- Johns Hopkins University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Stockwell, Brent R
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2014-05-20
- Volume
- 3
- Pages
- e02523-e02523
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4054777
- OpenAlex
- W2163294546
- Cited by
- 2,088
- References
- 69
- Citations by year
- 2026: 195 · 2025: 257 · 2024: 352 · 2023: 303 · 2022: 298 · 2021: 250 · 2020: 157 · 2019: 102 · 2018: 65 · 2017: 49 · 2016: 32 · 2015: 23 · 2014: 4
- FWCI
- 29.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Howard Hughes Medical Institute (Brent Stockwell Award)
- National Institutes of Health (5R01CA097061, 5R01GM085081 and R01CA161061, 1K99CA166517-01)
- New York Stem Cell Science (C026715)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- system xc-, cystine-glutamate exchange, erastin, sorafenib, endoplasmic reticulum stress, ferroptosis, CHAC1, pharmacodynamic biomarkers, kinase inhibitors, drug-induced adverse events, glutathione metabolism
- MeSH terms
- Sorafenib, Cell Line, Cell Separation, Cystine, Humans, Iron, Niacinamide, Phenylurea Compounds, Piperazines, Structure-Activity Relationship, 20-Hydroxysteroid Dehydrogenases, Biomarkers, Up-Regulation, Apoptosis, Sequence Analysis, RNA, Glutamic Acid, Amino Acid Transport System y+, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Transcriptome, Endoplasmic Reticulum Stress
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