[1]宋自崇 王静艺 张黎军.铁死亡在阿霉素心肌病中的作用机制[J].心血管病学进展,2024,(4):307.[doi:10.16806/j.cnki.issn.1004-3934.2024.04.005]
 SONG Zichong,WANG Jingyi,ZHANG Lijun.Mechanisms of ferroptosis in doxorubicin-induced cardiomyopathy[J].Advances in Cardiovascular Diseases,2024,(4):307.[doi:10.16806/j.cnki.issn.1004-3934.2024.04.005]





Mechanisms of ferroptosis in doxorubicin-induced cardiomyopathy
宋自崇1 王静艺 2 张黎军 1
(1.武汉大学人民医院老年病科,湖北 武汉430060;2.华中科技大学同济医学院附属同济医院神经内科,湖北 武汉 430030)
SONG Zichong1WANG Jingyi2ZHANG Lijun1
(1.Department of Geriatrics,Renmin Hospital of Wuhan University,Wuhan 430060,Hubei,China2.Department of Neurology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,Hubei,China)
FerroptosisDoxorubicin-induced cardiomyopathyMechanism
Doxorubicin (DOX) is the most widely used antitumor drug ,but its cardiotoxicity limits clinical efficacy. DOX can cause cardiomyocyte loss,progressive cardiac enlargement,and irreversible myocardial injury,ultimately leading to dilated cardiomyopathy and congestive heart failure,called DOX-induced cardiomyopathy (DIC). Several recent studies have reported the involvement of a new type of regulated cell death,ferroptosis,in its pathogenesis. This review describes the major mechanisms of ferroptosis and summarize the mechanisms of iron overload,PRMT4,Sirt1/Nrf2/Keap1 pathway,FUNDC2,and METTL14 mediated ferroptosis in DIC,aiming to gain further insights into the pathophysiological mechanisms of DIC,and to provide a new and potentially effective target for DIC treatment and prevention


[1] Hawas SS,El-Sayed SM,Elzahhar PA,et al. New 2-alkoxycyanopyridine derivatives as inhibitors of EGFR,HER2,and DHFR:synthesis,anticancer evaluation,and molecular modeling studies[J]. Bioorg Chem,2023,141:106874.

[2] Shipra,Tembhre MK,Hote MP,et al. PGC-1α agonist rescues doxorubicin-induced cardiomyopathy by mitigating the oxidative stress and necroptosis[J]. Antioxidants (Basel),2023,12(9):1720.

[3] Robert Li Y ,Traore K,Zhu H. Novel molecular mechanisms of doxorubicin cardiotoxicity:latest leading-edge advances and clinical implications[J]. Mol Cell Biochem,2023.DOI:10.1007/s11010-023-04783-3.

[4] Dixon SJ,Lemberg KM,Lamprecht MR,et al. Ferroptosis:an iron-dependent form of nonapoptotic cell death[J]. Cell,2012,149(5):1060-1072.

[5] Zeidan RS,Han SM,Leeuwenburgh C,et al. Iron homeostasis and organismal aging[J]. Ageing Res Rev,2021,72:101510.

[6] Dutt S,Hamza I,Bartnikas TB. Molecular mechanisms of iron and heme metabolism[J]. Annu Rev Nutr,2022,42:311-335.

[7] Zhao T,Yang Q,Xi Y,et al. Ferroptosis in rheumatoid arthritis:a potential therapeutic strategy[J]. Front Immunol,2022,13:779585.

[8] Stockwell BR. Ferroptosis turns 10: emerging mechanisms,physiological functions,and therapeutic applications[J]. Cell,2022,185(14):2401-2421.

[9] Xu S,He Y,Lin L,et al. The emerging role of ferroptosis in intestinal disease[J]. Cell Death Dis,2021,12(4):289.

[10] Tang D,Chen X,Kang R,et al. Ferroptosis:molecular mechanisms and health implications[J]. Cell Res,2021,31(2):107-125.

[11] Jiang X,Stockwell BR,Conrad M. Ferroptosis:mechanisms,biology and role in disease[J]. Nat Rev Mol Cell Biol,2021,22(4):266-282.

[12] Zhang X,Hou L,Guo Z,et al. Lipid peroxidation in osteoarthritis:focusing on 4-hydroxynonenal, malondialdehyde ,and ferroptosis[J]. Cell Death Discov,2023,9(1):320.

[13] Nishida Xavier da Silva T,Friedmann Angeli JP,Ingold I. GPX4:old lessons,new features[J]. Biochem Soc Trans,2022,50(3):1205-1213.

[14] Xu C,Sun S,Johnson T,et al. The glutathione peroxidase Gpx4 prevents lipid peroxidation and ferroptosis to sustain Treg cell activation and suppression of antitumor immunity[J]. Cell Rep,2021,35(11):109235.

[15] Niu B,Liao K,Zhou Y,et al. Application of glutathione depletion in cancer therapy:enhanced ROS-based therapy,ferroptosis,and chemotherapy[J]. Biomaterials,2021,277:121110.

[16] Liu MR,Zhu WT,Pei DS. System Xc-: a key regulatory target of ferroptosis in cancer[J]. Invest New Drugs,2021,39(4):1123-1131.

[17] Liu J,Kang R,Tang D. Signaling pathways and defense mechanisms of ferroptosis[J]. FEBS J,2022,289(22):7038-7050.

[18] Li S,He Y,Chen K,et al. RSL3 drives ferroptosis through NF-κB pathway activation and GPX4 depletion in glioblastoma[J]. Oxid Med Cell Longev,2021,2021:2915019.

[19] Costa I,Barbosa DJ,Benfeito S,et al. Molecular mechanisms of ferroptosis and their involvement in brain diseases[J]. Pharmacol Ther,2023,244:108373.

[20] Sun Y,Berleth N,Wu W,et al. Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells[J]. Cell Death Dis,2021,12(11):1028.

[21] Tadokoro T,Ikeda M,Ide T,et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity[J]. JCI Insight,2023,8(6): e169756.

[22] Du Y,Guo Z. Recent progress in ferroptosis:inducers and inhibitors[J]. Cell Death Discov,2022,8(1):501.

[23] Fang X,Wang H,Han D,et al. Ferroptosis as a target for protection against cardiomyopathy[J]. Proc Natl Acad Sci U S A,2019,116(7):2672-2680.

[24] Zhong Y,Wang Y,Li X,et al. PRMT4 facilitates white adipose tissue browning and thermogenesis by methylating PPARγ[J]. Diabetes,2023,72(8):1095-1111.

[25] Wang Y,Yan S,Liu X,et al. PRMT4 promotes ferroptosis to aggravate doxorubicin-induced cardiomyopathy via inhibition of the Nrf2/GPX4 pathway[J]. Cell Death Differ,2022,29(10):1982-1995.

[26] Ge MH,Tian H,Mao L,et al. Zinc attenuates ferroptosis and promotes functional recovery in contusion spinal cord injury by activating Nrf2/GPX4 defense pathway[J]. CNS Neurosci Ther,2021,27(9):1023-1040.

[27] Opstad TB,Papotti B,?kra S,et al. Sirtuin1,not NAMPT,possesses anti-inflammatory effects in epicardial,pericardial and subcutaneous adipose tissue in patients with CHD[J]. J Transl Med,2023,21(1):644.

[28] Wang AJ,Tang Y,Zhang J,et al. Cardiac SIRT1 ameliorates doxorubicin-induced cardiotoxicity by targeting sestrin 2[J]. Redox Biol,2022,52:102310.

[29] Wu YZ,Zhang L,Wu ZX,et al. Berberine ameliorates doxorubicin-induced cardiotoxicity via a SIRT1/p66Shc-mediated pathway[J]. Oxid Med Cell Longev,2019,2019:2150394.

[30] Liu D,Ma Z,Xu L,et al. PGC1α activation by pterostilbene ameliorates acute doxorubicin cardiotoxicity by reducing oxidative stress via enhancing AMPK and SIRT1 cascades[J]. Aging(Albany NY),2019,11(22):10061-10073.

[31] Wang W,Zhong X,Fang Z,et al. Cardiac sirtuin1 deficiency exacerbates ferroptosis in doxorubicin-induced cardiac injury through the Nrf2/Keap1 pathway[J]. Chem Biol Interact,2023,377:110469.

[32] Ulasov AV,Rosenkranz AA,Georgiev GP,et al. Nrf2/Keap1/ARE signaling:towards specific regulation[J]. Life Sci,2022,291:120111.

[33] Tanase DM,Gosav EM,Anton MI,et al. Oxidative stress and NRF2/KEAP1/ARE pathway in diabetic kidney disease(DKD):new perspectives[J]. Biomolecules,2022,12(9):1227.

[34] Mao Y,Ren J,Yang L. FUN14 domain containing 1 (FUNDC1):a promising mitophagy receptor regulating mitochondrial homeostasis in cardiovascular diseases[J]. Front Pharmacol,2022,13:887045.

[35] Ta N,Qu C,Wu H,et al. Mitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy[J]. Proc Natl Acad Sci U S A,2022,119(36):e2117396119.

[36] Wu Y,Zhan S,Xu Y,et al. RNA modifications in cardiovascular diseases,the potential therapeutic targets[J]. Life Sci,2021,278:119565.

[37] Cheng Y,Wang M,Zhou J,et al. The important role of N6-methyladenosine RNA modification in non-small cell lung cancer[J]. Genes(Basel),2021,12(3):440.

[38] Guo W,Zhang C,Feng P,et al. M6A methylation of DEGS2,a key ceramide-synthesizing enzyme,is involved in colorectal cancer progression through ceramide synthesis[J]. Oncogene,2021,40(40):5913-5924.

[39] Zhuang S,Ma Y,Zeng Y,et al. METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis[J]. Cell Biol Toxicol,2023,39(3):1015-1035.

[40] Cagle P,Qi Q,Niture S,et al. KCNQ1OT1:an oncogenic long noncoding RNA[J]. Biomolecules,2021,11(11):1602.


[1]袁明明 赖松青 张泽宇 吴起才.铁死亡在脓毒症心脏功能损伤中的研究进展[J].心血管病学进展,2022,(1):26.[doi:10.16806/j.cnki.issn.1004-3934.2022.01.007]
 YUAN mingmingLAI SongqingZHANG ZeyuWU Qicai.Ferroptosis in Cardiac Function Impairment in Sepsis[J].Advances in Cardiovascular Diseases,2022,(4):26.[doi:10.16806/j.cnki.issn.1004-3934.2022.01.007]
[2]彭石 马茜钰 张丹 张兆元 张锦.铁死亡在心肌缺血再灌注损伤中的作用及靶向治疗研究进展[J].心血管病学进展,2022,(4):357.[doi:10.16806/j.cnki.issn.1004-3934.2022.04.017]
 PENG Shi,MA Qianyu,ZHANG Dan,et al.Role and Targeted Treatment of Ferroptosis?n Myocardial Ischemia Reperfusion Injury[J].Advances in Cardiovascular Diseases,2022,(4):357.[doi:10.16806/j.cnki.issn.1004-3934.2022.04.017]
[3]彭可玲 贾晓艳 王华 刘永铭.铁死亡与心力衰竭的研究进展[J].心血管病学进展,2022,(5):432.[doi:10.16806/j.cnki.issn.1004-3934.2022.05.012]
 PENG Keling,JIA Xiaoyan,WANG Hua,et al.Ferroptosis and Heart Failure[J].Advances in Cardiovascular Diseases,2022,(4):432.[doi:10.16806/j.cnki.issn.1004-3934.2022.05.012]
[4]邵亚兰 马继鹏 卢林鹤 熊祥 马燕燕 刘金成 杨剑.铁死亡与铁自噬在中的研究进展[J].心血管病学进展,2022,(9):787.[doi:10.16806/j.cnki.issn.1004-3934.2022.09.005]
 SHAO Yalan,MA Jipeng,LU Linhe,et al.Ferroptosis and Ferritinophagy in Cardiovascular Disease[J].Advances in Cardiovascular Diseases,2022,(4):787.[doi:10.16806/j.cnki.issn.1004-3934.2022.09.005]
[5]孙悦 付松波 李亦兰.心肌细胞铁死亡及其检测方法[J].心血管病学进展,2023,(2):167.[doi:10.16806/j.cnki.issn.1004-3934.2023.02.016]
 SUN Yue,FU Songbo,LI Yilan.Methods for the Detection of Ferroptosis in Cardiomyocytes[J].Advances in Cardiovascular Diseases,2023,(4):167.[doi:10.16806/j.cnki.issn.1004-3934.2023.02.016]
[6]叶宇恒 钱玲玲 王如兴 李库林.心肌缺血再灌注损伤中铁死亡的调控机制研究进展[J].心血管病学进展,2023,(5):416.[doi:10.16806/j.cnki.issn.1004-3934.2023.05.008]
 YE Yuheng,QIAN Lingling,WANG Ruxing,et al.Regulatory Mechanisms of Ferroptosis in Myocardial Ischemia Reperfusion Injury[J].Advances in Cardiovascular Diseases,2023,(4):416.[doi:10.16806/j.cnki.issn.1004-3934.2023.05.008]
[7]王文杰 杨嘉馨 丁耀东 王可馨 牛佳龙 葛海龙.铁死亡在心血管疾病中的研究进展[J].心血管病学进展,2023,(5):420.[doi:10.16806/j.cnki.issn.1004-3934.2023.05.009]
 WANG Wenjie,YANG Jiaxin,DING Yaodong,et al.Ferroptosis in Cardiovascular Disease[J].Advances in Cardiovascular Diseases,2023,(4):420.[doi:10.16806/j.cnki.issn.1004-3934.2023.05.009]
[8]于永丽 李艳 高奋.铁死亡在血管紧张素Ⅱ诱导的心肌肥大中的作用研究进展[J].心血管病学进展,2023,(12):1116.[doi:10.16806/j.cnki.issn.1004-3934.2023.12.014]
 YU Yongli,LI Yan,GAO Fen.Ferroptosis in Angiotensin-Induced Cardiac hypertrophy[J].Advances in Cardiovascular Diseases,2023,(4):1116.[doi:10.16806/j.cnki.issn.1004-3934.2023.12.014]
[9]李心瑶 陈俊 李灼.脓毒症心肌病的发病机制研究进展[J].心血管病学进展,2024,(1):44.[doi:10.16806/j.cnki.issn.1004-3934.2023.01.012]
 LI Xinyao,CHEN Jun,LI Zhuo.Pathogenesis of Septic Cardiomyopathy[J].Advances in Cardiovascular Diseases,2024,(4):44.[doi:10.16806/j.cnki.issn.1004-3934.2023.01.012]
[10]赵 珂 陈晓姝 魏希进 张 娟 刘 杨 卞雨敬 袁 杰.铁死亡的调控机制及其在蒽环类药物心脏毒性中的研究进展[J].心血管病学进展,2024,(3):261.[doi:10.16806/j.cnki.issn.1004-3934.202.03.016]
 First Clinical Medical College,Shandong University of Traditional Chinese Medicine,Jinan 0000,et al.Regulatory Mechanism of Ferroptosis and Its Progress in Anthracycline-Induced Cardiotoxicity[J].Advances in Cardiovascular Diseases,2024,(4):261.[doi:10.16806/j.cnki.issn.1004-3934.202.03.016]

更新日期/Last Update: 2024-05-31