ArticleScientific reports2024
NFE2L2 and SLC25A39 drive cuproptosis resistance through GSH metabolism.
Article in Scientific reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed.
- Effects of cuproptosis and its application in inflammatory bowel disease (Review).International journal of molecular medicine · 2026Review
- Cuproptosis in Ischemic Stroke: Molecular Mechanisms and Therapeutic Potential.Molecules (Basel, Switzerland) · 2026Review
- Copper homeostasis and cuproptosis rewire the tumor microenvironment: mechanisms, immune modulation, and therapeutic opportunities.Journal of hematology & oncology · 2026Review
- Inhibition of ferroptosis via SLC25A39-NRF2 axis drives Osimertinib resistance in lung adenocarcinoma.Cellular and molecular life sciences : CMLS · 2026Article
- Nrf2 Activators in Parkinson's Disease: Modulating Mitophagy and Regulating Cuproptosis.Molecular neurobiology · 2026Review
- Emerging role of copper in the pathophysiology of spinal cord injury.Neural regeneration research · 2026Article
- Mitochondrial lipid remodeling in sepsis-associated acute kidney injury: a cardiolipin-centered convergence framework.Archives of toxicology · 2026Review
- Targeting Cuproptosis and Ferroptosis via a ROS-Responsive Nanoplatform for Enhanced Synergistic Therapy Against Hepatocellular Carcinoma.Antioxidants (Basel, Switzerland) · 2026Article
- Dual activation of cuproptosis and excessive autophagy by copper-bismuth metal-organic frameworks-loaded detachable microneedles in oral leukoplakia.Materials today. Bio · 2026Article
- [Role of programmed cell death in platinum resistance in ovarian cancer].Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2026Review
- Metabolic pathways and cell death modalities in diabetic complications: unraveling pyroptosis, ferroptosis, cuproptosis, and disulfidptosis.Cell death discovery · 2026Review
- Immune Checkpoint Inhibitors and Immunomodulators for Cancer Immunotherapy: Insights Into Resistance and Therapeutic Strategies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Research Progress on Elesclomol-Induced Cuproptosis for Antitumor Effects.Biomedicines · 2026Review
- The interactions of copper, glutamate, and cuproptosis: insights into brain health and Alzheimer's disease pathology.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2026Review
- Cuproptosis in inflammation and cancer: molecular mechanisms and therapeutic targets.Molecular cancer · 2026Review
- Morphable 'Stitched' Sensors for Simultaneous Spatiotemporal Tracking of Correlated Bioanalytes in Living Cells.JACS Au · 2026Article
- Novel Strategy for Cancer Therapy Proposal Based on Effects and Mechanisms of Targeting Cuproptosis by Polyphenols-A Narrative Review.Nutrients · 2026Review
- The p21 resilience network: a conceptual framework linking senescence to ferroptosis and cuproptosis resistance.NPJ systems biology and applications · 2026Review
- Primary tissue metabolic fingerprinting for efficient diagnosis of lymph node metastasis and metabolic reprogramming mechanisms in colorectal cancer.Materials today. Bio · 2026Article
- From molecular crosstalk to precision therapy: targeting ferroptosis and cuproptosis in oral squamous cell carcinoma.Frontiers in oncology · 2026Review
Corrections and comments
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cuproptosis is a recently discovered form of regulated cell death triggered by mitochondrial copper accumulation and proteotoxic stress. Here, we provide the first evidence that glutathione (GSH), a major non-protein thiol in cells, acts as a cuproptosis inhibitor in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, GSH inhibits cuproptosis by chelating copper, contrasting its role in blocking ferroptosis by inhibiting lipid peroxidation. The classical cuproptosis inducer, ES-Cu (elesclomol plus copper), increases the protein stability of the transcription factor NFE2L2 (also known as NRF2), leading to the upregulation of gene expression of glutamate-cysteine ligase modifier subunit (GCLM) and glutamate-cysteine ligase catalytic subunit (GCLC). GCLM and GCLC are rate-limiting enzymes in GSH synthesis, and increased GSH is transported into mitochondria via the solute carrier family 25 member 39 (SLC25A39) transporter. Consequently, genetic inhibition of the NFE2L2-GSH-SLC25A39 pathway enhances cuproptosis-mediated tumor suppression in cell culture and in mouse tumor models. These findings not only reveal distinct mechanisms of GSH in inhibiting cuproptosis and ferroptosis, but also suggest a potential combination strategy to suppress PDAC tumor growth.
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