Published March 22, 2023 - More info
Doxorubicin (DOX), a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicin-induced cardiomyopathy (DIC). This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis. However, the molecular mechanism underlying this cardiotoxicity is yet to be fully elucidated. Here, we show that DOX downregulated glutathione peroxidase 4 (GPx4) and induced excessive lipid peroxidation through DOX-Fe2+ complex in mitochondria, leading to mitochondria-dependent ferroptosis; we also show that mitochondria-dependent ferroptosis is a major cause of DOX cardiotoxicity. In DIC mice, the left ventricular ejection fraction was significantly impaired, and fibrosis and TUNEL+ cells were induced at day 14. Additionally, GPx4, an endogenous regulator of ferroptosis, was downregulated, accompanied by the accumulation of lipid peroxides, especially in mitochondria. These cardiac impairments were ameliorated in GPx4 Tg mice and exacerbated in GPx4 heterodeletion mice. In cultured cardiomyocytes, GPx4 overexpression or Fe2+ reduction in mitochondria prevented DOX-induced ferroptosis, demonstrating that DOX triggered ferroptosis in mitochondria. Furthermore, concomitant inhibition of ferroptosis and apoptosis with ferrostatin-1 and zVAD-FMK fully prevented DOX-induced cardiomyocyte death. Our findings suggest that mitochondria-dependent ferroptosis plays a key role in progression of DIC and that ferroptosis is the major form of regulated cell death in DOX cardiotoxicity.
Tomonori Tadokoro, Masataka Ikeda, Tomomi Ide, Hiroko Deguchi, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Shouji Matsushima, Tomoko Koumura, Ken-ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui
Original citation: JCI Insight. 2020;5(9):e132747. https://doi.org/10.1172/jci.insight.132747
Citation for this corrigendum: JCI Insight. 2023;8(6):e169756. https://doi.org/10.1172/jci.insight.169756
The authors recently became aware that the Mito-FerroGreen (MFG) used in this study is not an Fe2+ chelator, but instead reduces Fe2+ via conversion to Fe3+. As MFG mediates reduction of Fe2+ and suppresses ferroptosis, the overall conclusions are not affected. For clarity, the authors have removed references to MFG-mediated chelation throughout, updated the Graphical Abstract, and renumbered the reference list to refer to Hirayama et al. (1) when first describing the use of MFG in the Results section. The text and Graphical Abstract have been updated in the HTML version and PDF. The Journal has also published an online version of the original article with the incorrect statements crossed out and the modified text printed in red (Supplemental File, Redaction).
The authors regret the errors.
See the related article at Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity.