biostudies-literatureYan GNHLBI NIH HHS482-501https://www.ebi.ac.uk/biostudies/studies/S-EPMC10940206biostudies-literatureUnknown134(5)<h4>Background</h4>Mitochondrial 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.<h4>Methods</h4>Using 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 ponatiCirculation researchIntegrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity.PMC10940206R00 HL130416R01 HL164729R01 HL149891R01 HL148756K99 HL130416R01 HL162584T32 HL007829R01 HL133080Ong SGPinho SKwon YJousma JDu XHan ZOng SBLee WHProsser BLYan GNukala SBfalseIntegrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity.<h4>Background</h4>Mitochondrial 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.<h4>Methods</h4>Using 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 ponati2024-01-01T00:00:00Z2024 Mar2025-04-03T23:32:28.35Z2025-04-03T23:32:28.35ZS-EPMC109402063832347410.1161/CIRCRESAHA.123.32368310.1161/circresaha.123.323683