{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T12:44:55Z","timestamp":1787834695258,"version":"build-2784847793"},"reference-count":46,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T00:00:00Z","timestamp":1731456000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Innovation"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Ibrutinib is a first\u2010line drug that targets Bruton's tyrosine kinase for the treatment of B cell cancer. However, cardiotoxicity induced by ibrutinib is a major side effect that limits its clinical use. This study aimed to investigate the mechanism of ibrutinib\u2010induced cardiotoxicity and evaluate the protective role of metformin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The study utilized male C57BL\/6\u2009J mice, which were administered ibrutinib at a dosage of 30\u2009mg\/kg\/day via oral gavage for 4 weeks to induce cardiotoxicity. Metformin was administered orally at 200\u2009mg\/kg\/day for 5 weeks, starting 1 week before ibrutinib treatment. Cardiac function was assessed using echocardiography and electrophysiological studies, including surface electrocardiography and epicardial electrical mapping. Blood pressure was measured using a tail\u2010cuff system. Western blot analysis was conducted to evaluate the activity of the PI3K\u2010AKT and AMPK pathways, along with apoptosis markers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>C57BL\/6\u2009J mice were treated with ibrutinib for 4 weeks to assess its effect on cardiac function. We observed that ibrutinib induced ventricular arrhythmia and abnormal conduction while reducing the left ventricular ejection fraction. Furthermore, pretreatment with metformin reversed ibrutinib\u2010induced cardiotoxicity. Mechanistically, ibrutinib decreased PI3K\u2010AKT activity, resulting in apoptosis of cardiomyocytes. Administration of metformin upregulated AMPK and PI3K\u2010AKT activity, which contributed to the improvement of cardiac function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The study concludes that metformin effectively mitigates ibrutinib\u2010induced cardiotoxicity, including ventricular arrhythmia and cardiac dysfunction, by enhancing AMPK and PI3K\u2010AKT pathway activity. These findings suggest that metformin holds potential as a therapeutic strategy to protect against the adverse cardiac effects associated with ibrutinib treatment, offering a promising approach for improving the cardiovascular safety of patients undergoing therapy for B cell cancers.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cai2.151","type":"journal-article","created":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T03:34:17Z","timestamp":1731555257000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mitigating Ibrutinib\u2010Induced Ventricular Arrhythmia and Cardiac Dysfunction With Metformin"],"prefix":"10.1002","volume":"4","author":[{"given":"Pengsha","family":"Li","sequence":"first","affiliation":[{"name":"Tianjin Key Laboratory of Ionic\u2010Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology Second Hospital of Tianjin Medical University Tianjin 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