ArticleRedox biology2021
Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis.
Article in Redox biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 183 papers, 2 of them syntheses that pooled it.
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Who cites it
183 citing papers in PubMed, 2 syntheses or guidelines pooled it, 319 citations in OpenAlex.
- Targeting Ferroptosis as the Achilles' Heel of Breast Cancer: Mechanisms and Therapeutic Opportunities from a Comprehensive Systematic Review.International journal of molecular sciences · 2025Pooled it
- Cuproptosis as a therapeutic target in cancer: a Systematic Review and bibliometric analysis of the research landscape.Frontiers in oncology · 2025Pooled it
- The role of copper and cuproptosis in digestive system cancers: novel therapeutic strategies and mechanistic insights.Cancer biology & therapy · 2026Review
- Antiproliferation and Anti-invasion Activity of Binuclear Copper(II) Complex in BRAFi-Resistant Melanoma Cells.ACS pharmacology & translational science · 2026Article
- Harnessing copper-iron crosstalk: A novel strategy to combat hepatocellular carcinoma.Medical oncology (Northwood, London, England) · 2026Review
- Recent advancements in NRF2-regulated ferroptosis modulation for targeted cancer therapy.Molecular biology reports · 2026Review
- Advances in ferroptosis and cuproptosis: implications for spinal cord injury.Molecular biology reports · 2026Review
- Article
- Review
- PROTAC-mediated regulation of programmed cell death: From molecular mechanisms to therapeutic breakthroughs.Innovation (Cambridge (Mass.)) · 2026Review
- Cuproptosis Inducers in Cancer Therapy: State of the Art and Challenges.Chemical record (New York, N.Y.) · 2026Review
- Crosstalk of thioredoxin system and programmed cell death: from pathophysiology to novel therapy.Redox biology · 2026Review
- Hydrogen sulfide regulation in redox homeostasis and programmed cell death: mechanistic insights and implications in cancer.Journal of advanced research · 2026Review
- Emerging role of copper in the pathophysiology of spinal cord injury.Neural regeneration research · 2026Article
- USP9X regulates copper-induced CASP9/CASP3/GSDME-dependent pyroptosis by deubiquitinating JAK1.Apoptosis : an international journal on programmed cell death · 2026Article
- Copper homeostasis and cuproptosis in cancer: mitochondrial metabolic dependency and nanomedicine-based therapeutic strategies.Apoptosis : an international journal on programmed cell death · 2026Review
- Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence.iScience · 2026Article
- Ferroptosis-Driven Senescence Loop as a Central Amplifier of Osteoarthritis Progression.Biomolecules & therapeutics · 2026Review
- CuET promotes cuproptosis and ferroptosis of lung cancer cells by interacting directly with polyunsaturated phospholipids.iScience · 2026Article
- Asialoglycoprotein receptor-mediated delivery of copper to hepatic tumors exerted inhibitory effect on tumor growth and progression.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2026Article
123 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hepatocellular carcinoma (HCC) is one of the paramount causes of cancer-related death worldwide. Despite recent advances have been made in clinical treatments of HCC, the general prognosis of patients remains poor. Therefore, it is imperative to develop a less toxic and more effective therapeutic strategy. Currently, series of cellular, molecular, and pharmacological experimental approaches were utilized to address the unrecognized characteristics of disulfiram (DSF), pursuing the goal of repurposing DSF for cancer therapy. We found that DSF/Cu selectively exerted an efficient cytotoxic effect on HCC cell lines, and potently inhibited migration, invasion, and angiogenesis of HCC cells. Importantly, we confirmed that DSF/Cu could intensively impair mitochondrial homeostasis, increase free iron pool, enhance lipid peroxidation, and eventually result in ferroptotic cell death. Of note, a compensatory elevation of NRF2 accompanies the process of ferroptosis, and contributes to the resistance to DSF/Cu. Mechanically, we found that DSF/Cu dramatically activated the phosphorylation of p62, which facilitates competitive binding of Keap1, thus prolonging the half-life of NRF2. Notably, inhibition of NRF2 expression via RNA interference or pharmacological inhibitors significantly facilitated the accumulation of lipid peroxidation, and rendered HCC cells more sensitive to DSF/Cu induced ferroptosis. Conversely, fostering NRF2 expression was capable of ameliorating the cell death activated by DSF/Cu. Additionally, DSF/Cu could strengthen the cytotoxicity of sorafenib, and arrest tumor growth both in vitro and in vivo, by simultaneously inhibiting the signal pathway of NRF2 and MAPK kinase. In summary, these results provide experimental evidence that inhibition of the compensatory NRF2 elevation strengthens HCC cells more vulnerable to DSF/Cu induced ferroptosis, which facilitates the synergistic cytotoxicity of DSF/Cu and sorafenib.
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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.