{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T01:57:57Z","timestamp":1792634277168,"version":"4.5.0"},"reference-count":47,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"758","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:p>Clinical use of doxorubicin (DOX) is limited because of its cardiotoxicity, referred to as DOX-induced cardiomyopathy (DIC). Mitochondria-dependent ferroptosis, which is triggered by iron overload and excessive lipid peroxidation, plays a pivotal role in the progression of DIC. Here, we showed that DOX accumulated in mitochondria by intercalating into mitochondrial DNA (mtDNA), inducing ferroptosis in an mtDNA content-dependent manner. In addition, DOX disrupted heme synthesis by decreasing the abundance of 5'-aminolevulinate synthase 1 (Alas1), the rate-limiting enzyme in this process, thereby impairing iron utilization, resulting in iron overload and ferroptosis in mitochondria in cultured cardiomyocytes. Alas1 overexpression prevented this outcome. Administration of 5-aminolevulinic acid (5-ALA), the product of Alas1, to cultured cardiomyocytes and mice suppressed iron overload and lipid peroxidation, thereby preventing DOX-induced ferroptosis and DIC. Our findings reveal that the accumulation of DOX and iron in mitochondria cooperatively induces ferroptosis in cardiomyocytes and suggest that 5-ALA can be used as a potential therapeutic agent for DIC.<\/jats:p>","DOI":"10.1126\/scisignal.abn8017","type":"journal-article","created":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T17:58:12Z","timestamp":1667325492000},"source":"Crossref","is-referenced-by-count":151,"title":["Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2107-3052","authenticated-orcid":true,"given":"Ko","family":"Abe","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan."},{"name":"Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu 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