ArticleEBioMedicine2021
Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin.
Article in EBioMedicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers.
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Who cites it
80 citing papers in PubMed, 135 citations in OpenAlex.
- Imbalance of the Regulated Cell Death and Autophagic Network: A Core Mechanism Driving Toxicological and Ischemic Myocardial Injury and a Target for Intervention with Traditional Chinese Medicine.Cardiovascular toxicology · 2026Review
- Ferroptosis: Newly Emerged Regulator for Human Disease.MedComm · 2026Review
- Phase Separation of TRIM21 Modulates PTPN14 Stability to Drive Flow-Dependent Endothelial Activation and Atherogenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Review
- Osthole attenuates trastuzumab-induced cardiotoxicity in mice by enhancing autophagy via regulating the p38MAPK/mTOR signaling pathway.Journal of traditional and complementary medicine · 2026Article
- The Regulatory Landscape of Ferroptosis and Iron Homeostasis: Pathophysiological Mechanisms and Therapeutic Horizons in Cardiovascular Disease.Drug design, development and therapy · 2026Review
- LRRK2 Mediates α-Synuclein-Induced Neuroinflammation and Ferroptosis through the p62-Keap1-Nrf2 Pathway in Parkinson's Disease.Inflammation · 2025Article
- Tectorigenin attenuates myocardial damage by doxorubicin-induced ferroptosis by activating the p62-Keap1-Nrf2/HO-1/GPX4 axis.Journal of traditional and complementary medicine · 2025Article
- Targeting ATF4-DDIT4/TXNIP induced mitochondrial dysfunction and ferroptosis: ISRIB as novel therapy for septic cardiomyopathy.Journal of translational medicine · 2025Article
- The effect of carvacrol on kidney injury caused by isopreterenol-induced myocardial infarction.BMC nephrology · 2025Article
- ELAVL1 promotes ferroptosis via the TRIM21/HOXD8 axis to inhibit osteogenic differentiation in congenital pseudoarticular tibia-derived mesenchymal stem cells.Journal of cell communication and signaling · 2025Article
- TRIM21 knockdown alleviates hemorrhage induced hepatic ischemia reperfusion injury by suppressing ferroptosis-induced NETs.Scientific reports · 2025Article
- TRIM21-mediated METTL3 degradation promotes PDAC ferroptosis and enhances the efficacy of Anti-PD-1 immunotherapy.Cell death & disease · 2025Article
- Pleiotropic role of GAS6 in cardioprotection against ischemia-reperfusion injury.Journal of advanced research · 2025Article
- Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects.Bone research · 2025Review
- Epigenetic regulation and post-translational modifications of ferroptosis-related factors in cardiovascular diseases.Clinical epigenetics · 2025Review
- Unveiling the Complexities: Exploring Mechanisms of Anthracyclineinduced Cardiotoxicity.Current cardiology reviews · 2025Review
- A comprehensive review on doxorubicin: mechanisms, toxicity, clinical trials, combination therapies and nanoformulations in breast cancer.Drug delivery and translational research · 2025Review
- Asiatic acid ameliorates doxorubicin-induced cardiotoxicity by promoting FPN-mediated iron export and inhibiting ferroptosis.Acta pharmacologica Sinica · 2025Article
- Progress in the study of the mechanism of ferroptosis in coronary heart disease and clinical intervention strategies.Frontiers in cardiovascular medicine · 2025Review
20 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 7 institutions in 2 countries.
Funding
Abstract
backgroundDoxorubicin, an anthracycline chemotherapeutic agent, is widely used in the treatment of many cancers. However, doxorubicin posts a great risk of adverse cardiovascular events, which are thought to be caused by oxidative stress. We recently reported that the ubiquitin E3 ligase TRIM21 interacts and ubiquitylates p62 and negatively regulates the p62-Keap1-Nrf2 antioxidant pathway. Therefore, we sought to determine the role TRIM21 in cardiotoxicity induced by oxidative damage.
methodsUsing TRIM21 knockout mice, we examined the effects of TRIM21 on cardiotoxicity induced by two oxidative damage models: the doxorubicin treatment model and the Left Anterior Descending (LAD) model. We also explored the underlying mechanism by RNA-sequencing of the heart tissues, and by treating the mouse embryonic fibroblasts (MEFs), immortalized rat cardiomyocyte line H9c2, and immortalized human cardiomyocyte line AC16 with doxorubicin.
findingsTRIM21 knockout mice are protected from heart failure and fatality in both the doxorubicin and LAD models. Hearts of doxorubicin-treated wild-type mice exhibit deformed mitochondria and elevated level of lipid peroxidation reminiscent of ferroptosis, which is alleviated in TRIM21 knockout hearts. Mechanistically, TRIM21-deficient heart tissues and cultured MEFs and H9c2 cells display enhanced p62 sequestration of Keap1 and are protected from doxorubicin-induced ferroptosis. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient TRIM21 mutants impedes the protection from doxorubicin-induced cell death.
interpretationOur study demonstrates that TRIM21 ablation protects doxorubicin-induced cardiotoxicity and illustrates a new function of TRIM21 in ferroptosis, and suggests TRIM21 as a therapeutic target for reducing chemotherapy-related cardiotoxicity.
fundingNIH (CA129536; DK108989): data collection, analysis. Shanghai Pujiang Program (19PJ1401900): data collection. National Natural Science Foundation (31971161): data collection. Department of Veteran Affairs (BX004083): data collection. Tianjin Science and Technology Plan Project (17ZXMFSY00020): data collection.
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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 Socratic graph.