Redox Signaling in Doxorubicin-Induced Ferroptosis

Doxorubicin is among the most widely used anticancer drugs; however, its clinical use is associated with cardiomyopathy and heart failure. Studies show ferroptosis as a pivotal form of cell death underlying doxorubicin cardiomyopathy. Recently, multiple redox signaling pathways have been discovered to underly doxorubicin-induced ferroptosis. This Cutting-Edge Research Highlights discusses these latest advances, focusing on pathways involving Nrf2/HO-1, GPx4, and Alas1/heme synthesis. (First online: February 19, 2023) REFERENCES Zhu H, Sarkar S, Scott L, Danelisen I, Trush MA, Jia Z, et al. Doxorubicin Redox biology: redox cycling, topoisomerase inhibition, and oxidative stress. React Oxyg Species (Apex) 2016; 1(3):189–98. doi: https://dx.doi.org/10.20455/ros.2016.835 Higgins AY, O'Halloran TD, Chang JD. Chemotherapy-induced cardiomyopathy. Heart Fail Rev 2015; 20(6):721–30. doi: https://dx.doi.org/10.1007/s10741-015-9502-y Page RL, 2nd, O'Bryant CL, Cheng D, Dow TJ, Ky B, Stein CM, et al. Drugs that may cause or exacerbate heart failure: a scientific statement from the American Heart Association. Circulation 2016; 134(6):e32–69. doi: https://dx.doi.org/10.1161/CIR.0000000000000426 Fang X, Wang H, Han D, Xie E, Yang X, Wei J, et al. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci USA 2019; 116(7):2672–80. doi: https://dx.doi.org/10.1073/pnas.1821022116 Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149(5):1060–72. doi: https://dx.doi.org/10.1016/j.cell.2012.03.042 Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA 2016; 113(34):E4966–75. doi: https://dx.doi.org/10.1073/pnas.1603244113 Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 2017; 13(1):81–90. doi: https://dx.doi.org/10.1038/nchembio.2238 Ichikawa Y, Ghanefar M, Bayeva M, Wu R, Khechaduri A, Naga Prasad SV, et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 2014; 124(2):617–30. doi: https://dx.doi.org/10.1172/JCI72931 Tadokoro T, Ikeda M, Ide T, Deguchi H, Ikeda S, Okabe K, et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight 2020; 5(9). doi: https://dx.doi.org/10.1172/jci.insight.132747 Abe K, Ikeda M, Ide T, Tadokoro T, Miyamoto HD, Furusawa S, et al. Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis. Sci Signal 2022; 15(758):eabn8017. doi: https://dx.doi.org/10.1126/scisignal.abn8017