ArticleCirculation research2024
Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity.
Article in Circulation research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 30 citations in OpenAlex.
- Luteolin Alleviates Axitinib-Induced Cardiomyocyte Apoptosis in Mice.Journal of biochemical and molecular toxicology · 2026Article
- Endothelial ATF4 attenuates hypertensive vascular damage via preserving mitochondrial redox homeostasis.Molecular and cellular biochemistry · 2026Article
- Cardio-Oncology in Cold Climates: Epidemiological Features, Bidirectional Interaction Mechanisms, and Integrated Management Strategies.Cardiovascular toxicology · 2026Review
- Lapatinib Induces Ferroptosis in Cardiomyocytes by Regulating ATF4/GPX4.Cardiovascular toxicology · 2026Article
- Cardiotoxicity of Targeted Therapies in Hematologic Malignancies: From Molecular Mechanisms to Clinical Management.Current treatment options in oncology · 2026Review
- Integrated Stress Response and Drug-Induced Acute Kidney Injury: Involvement of Activating ATF4-STAT1-GBP2 Signaling.Journal of the American Society of Nephrology : JASN · 2026Article
- VCPIP1 drives diabetic cardiomyopathy by deubiquitinating AMPKγ1 and preventing AMPKα-γ subunit assembly in cardiomyocytes.Signal transduction and targeted therapy · 2026Article
- A Ponatinib-Associated Transcriptomic Signature: Implications for Cardiovascular Toxicity.International journal of molecular sciences · 2026Article
- Article
- Ponatinib confers adult human cardiomyocyte toxicity via inhibition of AKT signaling.Physiological reports · 2026Article
- Caught in the crossfire: cardiac complications of cancer therapy.The Journal of clinical investigation · 2026Review
- Review
- The Role of Mitochondrial Quality Control in Manganese-induced Neurotoxicity.Neurotoxicity research · 2025Review
- BMP-7 Treatment Ameliorates PTEN-Akt Mediated Apoptosis and Adverse Cardiac Remodeling in Ponatinib-Induced Cardiotoxicity.Pharmaceuticals (Basel, Switzerland) · 2025Article
- The ATF4-glutamine axis: a central node in cancer metabolism, stress adaptation, and therapeutic targeting.Cell death discovery · 2025Review
- Update on preclinical models of cancer therapy-related cardiac dysfunction: Challenges and perspectives. A scientific statement of the Heart Failure Association (HFA) of the ESC, the ESC Council of Cardio-Oncology, and the ESC Working Group on Cellular Biology of the Heart.European journal of heart failure · 2025Review
- Sotorasib-impaired degradation of NEU1 contributes to cardiac injury by inhibiting AKT signaling.Cell death discovery · 2025Article
- Canagliflozin differentially modulates carfilzomib-induced endoplasmic reticulum stress in multiple myeloma and endothelial cells.Archives of toxicology · 2025Article
- Current Knowledge of the Integrated Stress Response in the Development and Management of Acute Myeloid Leukemia: A Novel Target with Encouraging Progress.Drug design, development and therapy · 2025Review
- The multifaceted role of mitochondria in cardiac function: insights and approaches.Cell communication and signaling : CCS · 2024Review
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Authors and funding
11 authors at 4 institutions in 5 countries.
Funding
Abstract
backgroundMitochondrial dysfunction is a primary driver of cardiac contractile failure; yet, the cross talk between mitochondrial energetics and signaling regulation remains obscure. Ponatinib, a tyrosine kinase inhibitor used to treat chronic myeloid leukemia, is among the most cardiotoxic tyrosine kinase inhibitors and causes mitochondrial dysfunction. Whether ponatinib-induced mitochondrial dysfunction triggers the integrated stress response (ISR) to induce ponatinib-induced cardiotoxicity remains to be determined.
methodsUsing human induced pluripotent stem cells-derived cardiomyocytes and a recently developed mouse model of ponatinib-induced cardiotoxicity, we performed proteomic analysis, molecular and biochemical assays to investigate the relationship between ponatinib-induced mitochondrial stress and ISR and their role in promoting ponatinib-induced cardiotoxicity.
resultsProteomic analysis revealed that ponatinib activated the ISR in cardiac cells. We identified GCN2 (general control nonderepressible 2) as the eIF2α (eukaryotic translation initiation factor 2α) kinase responsible for relaying mitochondrial stress signals to trigger the primary ISR effector-ATF4 (activating transcription factor 4), upon ponatinib exposure. Mechanistically, ponatinib treatment exerted inhibitory effects on ATP synthase activity and reduced its expression levels resulting in ATP deficits. Perturbed mitochondrial function resulting in ATP deficits then acts as a trigger of GCN2-mediated ISR activation, effects that were negated by nicotinamide mononucleotide, an NAD
conclusionsNeutralizing ISR hyperactivation could prevent or reverse ponatinib-induced cardiotoxicity. The findings that compromised ATP production potentiates GCN2-mediated ISR activation have broad implications across various cardiac diseases. Our results also highlight an unanticipated role of ponatinib in causing direct activation of a kinase target despite its role as an ATP-competitive kinase inhibitor.
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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 OpenQuestion graph.