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Previous studies have suggested that febuxostat was associated with a higher risk of cardiovascular events, including atrial fibrillation, compared with allopurinol, another anti-hyperuricemia drug. Whereas in our clinical practice, we identified 2 cases of febuxostat-associated ventricular tachycardia (VT) events. The proarrhythmogenic effects of febuxostat on human cardiomyocytes and underlined mechanisms remain poorly understood. In this study, we employed real-time cell analysis and calcium transient to investigate the effects of febuxostat on the cytotoxicity and electrophysiology properties of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Up to 10\u2009\u03bcM febuxostat treatment did not show toxicity to cell viability. However, 48-h febuxostat exposure generated dose-dependent increased irregular calcium transients and decreased calcium transient amplitude. Furthermore, RNA-seq analysis indicated that the MAPK signaling pathway was enriched in the febuxostat-treated group, especially the protein kinases c-Jun N-terminal kinase (JNK). Western blotting of 3 main protein kinases demonstrated that JNK activation is related to febuxostat-induced arrhythmia rather than extracellular signal regulated kinases (ERK) or p38. The dysfunctional calcium dynamics of febuxostat-treated hiPSC-CMs could be ameliorated by SP600125, the inhibitor of JNK. In conclusion, our study demonstrated that febuxostat increases the predisposition to ventricular arrhythmia by dysregulating calcium dynamics.<\/jats:p>","DOI":"10.1093\/toxsci\/kfac073","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T11:48:44Z","timestamp":1658490524000},"page":"216-224","source":"Crossref","is-referenced-by-count":7,"title":["Febuxostat Increases Ventricular Arrhythmogenesis Through Calcium Handling Dysregulation in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes"],"prefix":"10.1093","volume":"189","author":[{"given":"Yue","family":"Zhu","sequence":"first","affiliation":[{"name":"Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University , Nanjing 210029, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingyu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University , Nanjing 210029, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Cai","sequence":"additional","affiliation":[{"name":"Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University , Nanjing 210029, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiqiao","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University , Nanjing 210029, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiyuan","family":"Qin","sequence":"additional","affiliation":[{"name":"Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University , Nanjing 210029, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hailei","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University , Nanjing 210029, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang","family":"Cui","sequence":"additional","affiliation":[{"name":"Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University , Nanjing 210029, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minglong","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University , Nanjing 210029, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,7,22]]},"reference":[{"key":"2022092808034083100_kfac073-B1","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1161\/CIRCRESAHA.112.272963","article-title":"Unrestrained p38 MAPK activation in Dusp1\/4 double-null mice induces cardiomyopathy","volume":"112","author":"Auger-Messier","year":"2013","journal-title":"Circ. 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