ArticleJCI insight2020
Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity.
Article in JCI insight, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 351 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
351 citing papers in PubMed, 609 citations in OpenAlex.
- Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia.Nature cancer · 2024Trial
- HydroMg attenuates doxorubicin-induced myocardial injury via promoting mitochondrial function.Medical gas research · 2027Article
- The cysteine metabolic regulation through CSE-transsulfuration pathway is essential in iron-induced oxidative damage of heart.Redox report : communications in free radical research · 2026Article
- Research progress of pancreatic cancer based on ferroptosis-cuproptosis interaction (Review).Oncology letters · 2026Review
- Breaking the cycle of fibrosis: Ferroptosis as a therapeutic target (Review).International journal of molecular medicine · 2026Review
- Genetic and Molecular Determinants of Cancer Therapy-Related Cardiovascular Toxicity.Cardiovascular toxicology · 2026Review
- Doxorubicin-induced hepatotoxicity: a multifaceted pathogenesis from mitochondrial collapse to immune remodeling and epigenetic memory.Archives of toxicology · 2026Review
- Ferroptosis as a target mechanism in heart and kidney disease.The Journal of clinical investigation · 2026Review
- Cardioprotective Potential of Grape-Derived Polyphenols in Cancer Therapy-Related Cardiotoxicity.International journal of molecular sciences · 2026Review
- Ferroptosis-Mitochondrial Crosstalk in Cardiomyocyte Death: The Cardiomyocyte Ferroptotic Amplification Circuit (CFAC) as a Proposed, Testable Systems Framework.Cardiovascular toxicology · 2026Review
- Oxidative Stress in Animals: A Systematic Analysis from Signaling Pathways to Biological Effects.Life (Basel, Switzerland) · 2026Review
- Babao Dan Improves Doxorubicin-Induced Cardiomyopathy by Activating Nrf2/GPX4 Signaling Pathway.Chinese journal of integrative medicine · 2026Article
- HSP47 in Mitochondria: Roles in Apoptosis, Signal Transduction, and Protein and Virus Transportation.Cells · 2026Review
- Ferroptosis: Newly Emerged Regulator for Human Disease.MedComm · 2026Review
- Calycosin Safeguards Mitochondrial Genomic Stability and Iron Homeostasis via the NRF2/NRF1-TFAM Axis to Mitigate Doxorubicin-Induced Cardiotoxicity.Antioxidants (Basel, Switzerland) · 2026Article
- Morroniside Attenuates Doxorubicin-Induced Cardiotoxicity by Activating the PI3K/AKT/Nrf2/HO-1 Pathway to Inhibit Ferroptosis and Oxidative Stress.Journal of biochemical and molecular toxicology · 2026Article
- Molecular mechanisms of iron metabolism and ferroptosis in cardiovascular diseases and intervention strategies targeting natural products (Review).Molecular medicine reports · 2026Review
- Dual-Metal Regulation of Cardiac Remodeling: Targeting the LOXL2-Ferroptosis Axis in Metal-Induced Cardiac Dysfunction.Cardiovascular toxicology · 2026Review
- Metainflammation, Mitochondrial Dysfunction, and Organokine Crosstalk: A Central Axis Linking Metabolic Syndrome to Cardiovascular Diseases.International journal of molecular sciences · 2026Review
- PET117 Deficiency Confers Ferroptosis Resistance Through ACSF2 Downregulation in Cervical Cancer.Antioxidants (Basel, Switzerland) · 2026Article
291 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
12 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Doxorubicin (DOX), a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicin-induced cardiomyopathy (DIC). This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis. However, the molecular mechanism underlying this cardiotoxicity is yet to be fully elucidated. Here, we show that DOX downregulated glutathione peroxidase 4 (GPx4) and induced excessive lipid peroxidation through DOX-Fe2+ complex in mitochondria, leading to mitochondria-dependent ferroptosis; we also show that mitochondria-dependent ferroptosis is a major cause of DOX cardiotoxicity. In DIC mice, the left ventricular ejection fraction was significantly impaired, and fibrosis and TUNEL+ cells were induced at day 14. Additionally, GPx4, an endogenous regulator of ferroptosis, was downregulated, accompanied by the accumulation of lipid peroxides, especially in mitochondria. These cardiac impairments were ameliorated in GPx4 Tg mice and exacerbated in GPx4 heterodeletion mice. In cultured cardiomyocytes, GPx4 overexpression or iron chelation targeting Fe2+ in mitochondria prevented DOX-induced ferroptosis, demonstrating that DOX triggered ferroptosis in mitochondria. Furthermore, concomitant inhibition of ferroptosis and apoptosis with ferrostatin-1 and zVAD-FMK fully prevented DOX-induced cardiomyocyte death. Our findings suggest that mitochondria-dependent ferroptosis plays a key role in progression of DIC and that ferroptosis is the major form of regulated cell death in DOX cardiotoxicity.
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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.