ArticleAutophagy2024
Inhibition of PRKAA/AMPK (Ser485/491) phosphorylation by crizotinib induces cardiotoxicity via perturbing autophagosome-lysosome fusion.
Article in Autophagy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 1 of them a synthesis that pooled it.
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Who cites it
33 citing papers in PubMed, 1 synthesis or guideline pooled it, 54 citations in OpenAlex.
- Evaluating the use of rodents as in vitro, in vivo and ex vivo experimental models for the assessment of tyrosine kinase inhibitor-induced cardiotoxicity: a systematic review.Archives of toxicology · 2025Pooled it
- Luteolin Alleviates Axitinib-Induced Cardiomyocyte Apoptosis in Mice.Journal of biochemical and molecular toxicology · 2026Article
- AKT (Ser473) suppression mediates ceritinib cardiotoxicity through autophagic flux impairment and mitochondrial injury.Acta pharmacologica Sinica · 2026Article
- Interaction between Regulated Cell Death Pathways and Core Cellular Processes: Unraveling the Molecular Mechanisms of Cardiotoxicity of Antitumor Drugs.Current treatment options in oncology · 2026Review
- Inhibition of Cathepsin B protects against vandetanib-induced hepato-cardiotoxicity by restoring lysosomal damage.International journal of biological sciences · 2026Article
- Pre-TACE CK-MB/CK Ratio as an Independent Prognostic Biomarker in Advanced Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2026Article
- Serum Metabolomic Profiles Predict Sensitivity and Toxicity to Platinum- Fluorouracil Chemotherapy in a Gastric Cancer Xenograft Model.Combinatorial chemistry & high throughput screening · 2026Article
- Increased Cardiovascular Risk With Lorlatinib in Patients With ALK-Mutated Lung Cancer: A Real-World Comparative Study.Journal of the American Heart Association · 2025Article
- Exploiting the cardioprotective potential of metformin against cardiotoxic agents.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Entrectinib binds to HMGB1 and activates cardiomyocyte autophagy by inhibiting OTUD5-MTORC1 signaling to induce cardiotoxicity.Autophagy · 2025Article
- AMPK/SIRT1/PGC-1α Signaling Pathway: Molecular Mechanisms and Targeted Strategies From Energy Homeostasis Regulation to Disease Therapy.CNS neuroscience & therapeutics · 2025Review
- From Gut to Heart: Targeting Trimethylamine N-Oxide as a Novel Strategy in Heart Failure Management.Biomolecules · 2025Review
- Plasma ALKAL2 levels are associated with coronary atherosclerosis in patients with type 2 diabetes mellitus.Cardiovascular diabetology · 2025Article
- Mitochondrial DNA Dysfunction in Cardiovascular Diseases: A Novel Therapeutic Target.Antioxidants (Basel, Switzerland) · 2025Review
- Fusion genes in cancers: Biogenesis, functions, and therapeutic implications.Genes & diseases · 2025Review
- Spatio-temporal processes in autophagosome-lysosome fusion.Medical review (2021) · 2025Review
- H 2 protects H9c2 cells from hypoxia/reoxygenation injury by inhibiting the Wnt/CX3CR1 signaling pathway.Medical gas research · 2025Article
- Cardiotoxicity of small-molecule kinase inhibitors in cancer therapy.Experimental hematology & oncology · 2025Review
- Disturbing Cholesterol/Sphingolipid Metabolism by Squalene Epoxidase Arises Crizotinib Hepatotoxicity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Targeting of arachidonic acid-modulated autophagy to enhance the sensitivity ofTranslational lung cancer research · 2025Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Crizotinib, a small-molecule tyrosine kinase inhibitor targeting ALK, MET and ROS1, is the first-line drug for ALK-positive metastatic non-small cell lung cancer and is associated with severe, sometimes fatal, cases of cardiac failure, which increases the risk of mortality. However, the underlying mechanism remains unclear, which causes the lack of therapeutic strategy. We established in vitro and in vivo models for crizotinib-induced cardiotoxicity and found that crizotinib caused left ventricular dysfunction, myocardial injury and pathological remodeling in mice and induced cardiomyocyte apoptosis and mitochondrial injury. In addition, we found that crizotinib prevented the degradation of MET protein by interrupting autophagosome-lysosome fusion and silence of MET or re-activating macroautophagy/autophagy flux rescued the cardiomyocytes death and mitochondrial injury caused by crizotinib, suggesting that impaired autophagy activity is the key reason for crizotinib-induced cardiotoxicity. We further confirmed that recovering the phosphorylation of PRKAA/AMPK (Ser485/491) by metformin re-activated autophagy flux in cardiomyocytes and metformin rescued crizotinib-induced cardiomyocyte injury and cardiac complications. In summary, we revealed a novel mechanism for crizotinib-induced cardiotoxicity, wherein the crizotinib-impaired autophagy process causes cardiomyocyte death and cardiac injury by inhibiting the degradation of MET protein, demonstrated a new function of impeded autophagosome-lysosome fusion in drugs-induced cardiotoxicity, pointed out the essential role of the phosphorylation of PRKAA (Ser485/491) in autophagosome-lysosome fusion and confirmed metformin as a potential therapeutic strategy for crizotinib-induced 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.