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Cardiomyocytes are the major functional units in the myocardium, and impairment of their viability and function plays a crucial role in cardiotoxic responses. Previous studies have indicated direct toxicity of ponatinib on cardiomyocytes, but the effect of ponatinib on adult human primary cardiomyocytes (hPCMs) remains unknown, largely due to sample scarcity and the technical challenges associated with the adult human cardiomyocyte model. Based upon our previous work establishing hPCMs as a pharmacologically competent model, we tested the direct toxicity of ponatinib on these cells. We reveal suppression of AKT, but not ERK, phosphorylation upon ponatinib treatment. Treatment of hPCMs with AKT inhibitor MK\u20102206 phenocopied ponatinib, while restoration of AKT signaling with UCL\u2010TRO\u20101938 or insulin partially rescued hPCMs from cell death, suggesting a potential protective effect.<\/jats:p>","DOI":"10.14814\/phy2.70877","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T11:48:13Z","timestamp":1776426493000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ponatinib confers adult human cardiomyocyte toxicity via inhibition of\n                    <scp>AKT<\/scp>\n                    signaling"],"prefix":"10.14814","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6245-9538","authenticated-orcid":false,"given":"Linna","family":"Guo","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences 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