Skip to main content
SpringerLink
Log in

Molecular mechanisms of ferroptosis in cardiovascular disease

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Ferroptosis is a newly recognized type of regulated cell death that is characterized by the accumulation of iron and lipid peroxides in cells. Studies have shown that ferroptosis plays a significant role in the pathogenesis of various diseases, including cardiovascular diseases. In cardiovascular disease, ferroptosis is associated with ischemia–reperfusion injury, myocardial infarction, heart failure, and atherosclerosis. The molecular mechanisms underlying ferroptosis include the iron-dependent accumulation of lipid peroxidation products, glutathione depletion, and dysregulation of lipid metabolism, among others. This review aims to summarize the current knowledge of the molecular mechanisms of ferroptosis in cardiovascular disease and discuss the potential therapeutic strategies targeting ferroptosis as a treatment for cardiovascular disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

Enquiries about data availability should be directed to the authors.

References

  1. Jiang XA-O, Stockwell BA-O, Conrad MA-O (2021) Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 22(4):266–282. https://doi.org/10.1038/s41580-020-00324-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Liang D, Minikes AM, Jiang X (2022) Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell 82(12):2215–2227. https://doi.org/10.1016/j.molcel.2022.03.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Qiu Y, Cao Y, Cao W, Jia Y, Lu N (2020) The application of ferroptosis in diseases. Pharmacol Res 159:104919. https://doi.org/10.1016/j.phrs.2020.104919

    Article  CAS  PubMed  Google Scholar 

  4. Fang XA-O, Ardehali H, Min J, Wang FA-O (2023) The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. Nat Rev Cardiol 20(1):7–23. https://doi.org/10.1038/s41569-022-00735-4

    Article  PubMed  Google Scholar 

  5. Guo Y, Lu C, Hu K, Cai C, Wang WA-O (2022) Ferroptosis in cardiovascular diseases: current status, challenges, and future perspectives. Biomolecules 12(3):390. https://doi.org/10.3390/biom12030390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yang X, Kawasaki NK, Min J, Matsui T, Wang F (2022) Ferroptosis in heart failure. J Mol Cell Cardiol 173:141–153. https://doi.org/10.1016/j.yjmcc.2022.10.004

    Article  CAS  PubMed  Google Scholar 

  7. Bai T, Li M, Liu Y, Qiao Z, Wang Z (2020) Inhibition of ferroptosis alleviates atherosclerosis through attenuating lipid peroxidation and endothelial dysfunction in mouse aortic endothelial cell. Free Radic Biol Med 160:92–102. https://doi.org/10.1016/j.freeradbiomed.2020.07.026

    Article  CAS  PubMed  Google Scholar 

  8. Zhao WA-O, Zhou YA-O, Xu TA-O, Wu QA-O (2021) Ferroptosis: opportunities and challenges in myocardial ischemia-reperfusion injury. Oxid Med Cell Longev 2021:9929687. https://doi.org/10.1155/2021/9929687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li Y, Feng D, Wang Z, Zhao Y, Sun R, Tian D, Liu D et al (2019) Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ 26(11):2284–2299. https://doi.org/10.1038/s41418-019-0299-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ajoolabady A, Aslkhodapasandhokmabad H, Libby P, Tuomilehto J, Lip GYH, Penninger JM, Richardson DR et al (2021) Ferritinophagy and ferroptosis in the management of metabolic diseases. Endocrinol Metab 32(7):444–462. https://doi.org/10.1016/j.tem.2021.04.010

    Article  CAS  Google Scholar 

  11. Hong M, Rong J, Tao X, Xu Y (2022) The emerging role of ferroptosis in cardiovascular diseases. Front Pharmacol 13:822083. https://doi.org/10.3389/fphar.2022.822083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wu H, Wang F, Ta N, Zhang T, Gao W (2021) The multifaceted regulation of mitochondria in ferroptosis. Life (Basel) 11(3):222. https://doi.org/10.3390/life11030222

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu S, Mao C, Kondiparthi L, Poyurovsky MV, Olszewski K, Gan BA-O (2022) A ferroptosis defense mechanism mediated by glycerol-3-phosphate dehydrogenase 2 in mitochondria. Proc Natl Acad Sci USA 119(26):e2121987119. https://doi.org/10.1073/pnas.2121987119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jang S, Chapa-Dubocq XR, Tyurina YY, St Croix CM, Kapralov AA, Tyurin VA, Bayır H et al (2021) Elucidating the contribution of mitochondrial glutathione to ferroptosis in cardiomyocytes. Redox Biol 45:102021. https://doi.org/10.1016/j.redox.2021.102021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Haarhaus MA-O, Cianciolo G, Barbuto SA-O, La Manna G, Gasperoni L, Tripepi G, Plebani MA-O et al (2022) Alkaline phosphatase: an old friend as treatment target for cardiovascular and mineral bone disorders in chronic kidney disease. Nutrients 14(10):2124. https://doi.org/10.3390/nu14102124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cardoso AC, Lam NT, Savla JJ, Nakada Y, Pereira AHM, Elnwasany A, Menendez-Montes I et al (2020) Mitochondrial substrate utilization regulates cardiomyocyte cell cycle progression. Nat Metab 2(2):167–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chan DC (2020) Mitochondrial dynamics and its involvement in disease. Annu Rev Pathol 15:235–259. https://doi.org/10.1146/annurev-pathmechdis-012419-032711

    Article  CAS  PubMed  Google Scholar 

  18. Jiao H, Jiang D, Hu X, Du W, Ji L, Yang Y, Li X et al (2021) Mitocytosis, a migrasome-mediated mitochondrial quality-control process. Cell 184(11):2896-2910.e13. https://doi.org/10.1016/j.cell.2021.04.027

    Article  CAS  PubMed  Google Scholar 

  19. Read AD, Bentley RE, Archer SL, Dunham-Snary KJ (2021) Mitochondrial iron–sulfur clusters: structure, function, and an emerging role in vascular biology. Redox Biol 47:102164. https://doi.org/10.1016/j.redox.2021.102164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fang XA-O, Wang HA-O, Han D, Xie E, Yang X, Wei J, Gu S et al (2019) Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci USA 116(7):2672–2680. https://doi.org/10.1073/pnas.1821022116

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kitakata H, Endo JA-O, Ikura H, Moriyama H, Shirakawa K, Katsumata Y, Sano M (2022) Therapeutic targets for dox-induced cardiomyopathy: role of apoptosis vs. ferroptosis. Int J Mol Sci 23(3):1414. https://doi.org/10.3390/ijms23031414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jelinek A, Heyder L, Daude M, Plessner M, Krippner S, Grosse R, Diederich WE et al (2018) Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis. Free Radic Biol Med 117:45–57. https://doi.org/10.1016/j.freeradbiomed.2018.01.019

    Article  CAS  PubMed  Google Scholar 

  23. Yang P, Luo X, Li J, Zhang T, Gao XA-O, Hua J, Li Y et al (2021) Ionizing radiation upregulates glutamine metabolism and induces cell death via accumulation of reactive oxygen species. Oxid Med Cell Longev 2021:5826932. https://doi.org/10.1155/2021/5826932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fiore A, Zeitler L, Russier M, Groß A, Hiller MK, Parker JL, Stier L et al (2022) Kynurenine importation by SLC7A11 propagates anti-ferroptotic signaling. Mol Cell 82(5):920-932.e7. https://doi.org/10.1016/j.molcel.2022.02.007

    Article  CAS  PubMed  Google Scholar 

  25. Mishima EA-O, Ito J, Wu ZA-OX, Nakamura T, Wahida A, Doll SA-O, Tonnus WA-O et al (2022) A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608(7924):778–783. https://doi.org/10.1038/s41586-022-05022-3

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xie LW, Cai S, Zhao TS, Li M, Tian Y (2020) Green tea derivative (-)-epigallocatechin-3-gallate (EGCG) confers protection against ionizing radiation-induced intestinal epithelial cell death both in vitro and in vivo. Free Radic Biol Med 161:175–186. https://doi.org/10.1016/j.freeradbiomed.2020.10.012

    Article  CAS  PubMed  Google Scholar 

  27. Yi H, Liu C, Shi J, Wang S, Zhang H, He Y, Tao J et al (2022) EGCG alleviates obesity-induced myocardial fibrosis in rats by enhancing expression of SCN5A. Front Cardiovasc Med 9:869279. https://doi.org/10.3389/fcvm.2022.869279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hinman A, Holst CR, Latham JC, Bruegger JJ, Ulas G, McCusker KP, Amagata A et al (2018) Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. PLoS ONE 13(8):e0201369. https://doi.org/10.1371/journal.pone.0201369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Averill-Bates DA (2023) The antioxidant glutathione. Vitam Horm 121:109–141. https://doi.org/10.1016/bs.vh.2022.09.002

    Article  CAS  PubMed  Google Scholar 

  30. Bajic VP, Van Neste C, Obradovic M, Zafirovic SA-O, Radak D, Bajic VA-O, Essack MA-O et al (2019) Glutathione “redox homeostasis” and its relation to cardiovascular disease. Oxid Med Cell Longev 2019:5028181. https://doi.org/10.1155/2019/5028181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fang X, Cai Z, Wang H, Han D, Cheng Q, Zhang P, Gao F et al (2020) Loss of cardiac ferritin H facilitates cardiomyopathy via Slc7a11-mediated ferroptosis. Circ Res 127(4):486–501. https://doi.org/10.1161/CIRCRESAHA.120.316509

    Article  CAS  PubMed  Google Scholar 

  32. Ta N, Qu C, Wu H, Zhang D, Sun T, Li Y, Wang J et al (2022) Mitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy. Proc Natl Acad Sci USA 119(36):e2117396119. https://doi.org/10.1073/pnas.2117396119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ye Y, Chen A, Li L, Liang Q, Wang S, Dong Q, Fu M et al (2022) Repression of the antiporter SLC7A11/glutathione/glutathione peroxidase 4 axis drives ferroptosis of vascular smooth muscle cells to facilitate vascular calcification. Kidney Int 102(6):1259–1275. https://doi.org/10.1016/j.kint.2022.07.034

    Article  CAS  PubMed  Google Scholar 

  34. Xu S, Wu B, Zhong B, Lin L, Ding Y, Jin X, Huang Z et al (2021) Naringenin alleviates myocardial ischemia/reperfusion injury by regulating the nuclear factor-erythroid factor 2-related factor 2 (Nrf2)/system xc-/glutathione peroxidase 4 (GPX4) axis to inhibit ferroptosis. Bioengineered 12(2):10924–10934. https://doi.org/10.1080/21655979.2021.1995994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kumar P, Osahon OW, Sekhar RA-OX (2022) GlyNAC (glycine and N-acetylcysteine) supplementation in mice increases length of life by correcting glutathione deficiency, oxidative stress, mitochondrial dysfunction, abnormalities in mitophagy and nutrient sensing, and genomic damage. Nutrients 14(5):1114. https://doi.org/10.3390/nu14051114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, Roberts MA et al (2019) The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575(7784):688–692. https://doi.org/10.1038/s41586-019-1705-2

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jia M, Qin D, Zhao C, Chai L, Yu Z, Wang W, Tong L et al (2020) Redox homeostasis maintained by GPX4 facilitates STING activation. Nat Immunol 21(7):727–735. https://doi.org/10.1038/s41590-020-0699-0

    Article  CAS  PubMed  Google Scholar 

  38. Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N et al (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16(12):1180–1191. https://doi.org/10.1038/ncb3064

    Article  CAS  PubMed  Google Scholar 

  39. Zhang Z, Tang J, Song J, Xie M, Liu Y, Dong Z, Liu X et al (2022) Elabela alleviates ferroptosis, myocardial remodeling, fibrosis and heart dysfunction in hypertensive mice by modulating the IL-6/STAT3/GPX4 signaling. Free Radic Biol Med 181:130–142. https://doi.org/10.1016/j.freeradbiomed.2022.01.020

    Article  CAS  PubMed  Google Scholar 

  40. Park TJ, Park JH, Lee GS, Lee JY, Shin JH, Kim MW, Kim YS et al (2019) Quantitative proteomic analyses reveal that GPX4 downregulation during myocardial infarction contributes to ferroptosis in cardiomyocytes. Cell Death Dis 10(11):835. https://doi.org/10.1038/s41419-019-2061-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang YA-O, Yan SA-O, Liu XA-O, Deng FA-O, Wang P, Yang L, Hu LA-O et al (2022) PRMT4 promotes ferroptosis to aggravate doxorubicin-induced cardiomyopathy via inhibition of the Nrf2/GPX4 pathway. Cell Death Differ 29(10):1982–1995. https://doi.org/10.1038/s41418-022-00990-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Feng Z, Qin Y, Huo F, Jian Z, Li X, Geng J, Li Y et al (2022) NMN recruits GSH to enhance GPX4-mediated ferroptosis defense in UV irradiation induced skin injury. Biochim Biophys Acta Mol Basis Dis 1868(1):166287. https://doi.org/10.1016/j.bbadis.2021.166287

    Article  CAS  PubMed  Google Scholar 

  43. Ursini F, Maiorino M (2020) Lipid peroxidation and ferroptosis: the role of GSH and GPx4. Free Radic Biol Med 152:175–185. https://doi.org/10.1016/j.freeradbiomed.2020.02.027

    Article  CAS  PubMed  Google Scholar 

  44. Fu C, Wu Y, Liu S, Luo C, Lu Y, Liu M, Wang L et al (2022) Rehmannioside A improves cognitive impairment and alleviates ferroptosis via activating PI3K/AKT/Nrf2 and SLC7A11/GPX4 signaling pathway after ischemia. J Ethnopharmacol 289:115021. https://doi.org/10.1016/j.jep.2022.115021

    Article  CAS  PubMed  Google Scholar 

  45. Hong H, Lin X, Xu Y, Tong T, Zhang J, He H, Yang L et al (2022) Cadmium induces ferroptosis mediated inflammation by activating Gpx4/Ager/p65 axis in pancreatic β-cells. Sci Total Environ 849:157819. https://doi.org/10.1016/j.scitotenv.2022.157819

    Article  ADS  CAS  PubMed  Google Scholar 

  46. Schwärzler J, Mayr L, Radlinger B, Grabherr F, Philipp M, Texler B, Grander C et al (2022) Adipocyte GPX4 protects against inflammation, hepatic insulin resistance and metabolic dysregulation. Int J Obes (Lond) 46(5):951–959. https://doi.org/10.1038/s41366-022-01064-9

    Article  CAS  PubMed  Google Scholar 

  47. Li Y, Wende AR, Nunthakungwan O, Huang Y, Hu E, Jin H, Boudina S, Dale Abel E, Jalili T (2012) Cytosolic, but not mitochondrial, oxidative stress is a likely contributor to cardiac hypertrophy resulting from cardiac specific GLUT4 deletion in mice. FEBS J 279(4):599–611. https://doi.org/10.1111/j.1742-4658.2011.08450.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang C, Yuan W, Hu A, Lin J, Xia Z, Yang CF, Li Y et al (2020) Dexmedetomidine alleviated sepsis-induced myocardial ferroptosis and septic heart injury. Mol Med Rep 22(1):175–184. https://doi.org/10.3892/mmr.2020.11114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Park E, Chung SW (2019) ROS-mediated autophagy increases intracellular iron levels and ferroptosis by ferritin and transferrin receptor regulation. Cell Death Dis 10(11):822. https://doi.org/10.1038/s41419-019-2064-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ma J, Zhang H, Chen Y, Liu X, Tian J, Shen W (2022) The role of macrophage iron overload and ferroptosis in atherosclerosis. Biomolecules 12(11):1702. https://doi.org/10.3390/biom12111702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sukhanov AA, Mamedov MD, Milanovsky GE, Salikhov KM, Semenov AY (2022) Changes in the electron transfer symmetry in the photosystem I reaction centers upon removal of iron–sulfur clusters. Biochem Mosc 87(10):1109–1118. https://doi.org/10.1134/S0006297922100042

    Article  CAS  Google Scholar 

  52. Montoro-Huguet MA-O, Santolaria-Piedrafita S, Cañamares-Orbis P, García-Erce JA-O (2021) Iron deficiency in celiac disease: prevalence, health impact, and clinical management. Nutrients 13(10):3437. https://doi.org/10.3390/nu13103437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wu X, Li Y, Zhang S, Zhou X (2021) Ferroptosis as a novel therapeutic target for cardiovascular disease. Theranostics 11(7):3052–3059. https://doi.org/10.7150/thno.54113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Li N, Jiang W, Wang W, Xiong R, Wu X, Geng Q (2021) Ferroptosis and its emerging roles in cardiovascular diseases. Pharmacol Res 166:105466. https://doi.org/10.1016/j.phrs.2021.105466

    Article  CAS  PubMed  Google Scholar 

  55. Xie LA-O, Fefelova N, Pamarthi SH, Gwathmey JK (2022) Molecular mechanisms of ferroptosis and relevance to cardiovascular disease. Cells 11(17):2726. https://doi.org/10.3390/cells11172726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Stocki P, Szary J, Rasmussen CLM, Demydchuk M, Northall L, Logan DB, Gauhar A et al (2021) Blood-brain barrier transport using a high affinity, brain-selective VNAR antibody targeting transferrin receptor 1. FASEB J 35(2):e21172. https://doi.org/10.1096/fj.202001787R

    Article  CAS  PubMed  Google Scholar 

  57. Xiao Z, Kong B, Fang J, Qin T, Dai C, Shuai W, Huang H (2021) Ferrostatin-1 alleviates lipopolysaccharide-induced cardiac dysfunction. Bioengineered 12(2):9367–9376. https://doi.org/10.1080/21655979.2021.2001913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Du W, Wang J, Zhou L, Zhou J, Feng L, Dou C, Zhang Q et al (2023) Transferrin-targeted iridium nanoagglomerates with multi-enzyme activities for cerebral ischemia-reperfusion injury therapy. Acta Biomater 166:524–535. https://doi.org/10.1016/j.actbio.2023.04.025

    Article  CAS  PubMed  Google Scholar 

  59. Yanatori I, Yasui Y, Noguchi Y, Kishi F (2015) Inhibition of iron uptake by ferristatin II is exerted through internalization of DMT1 at the plasma membrane. Cell Biol Int 39(4):427–434. https://doi.org/10.1002/cbin.10403

    Article  CAS  PubMed  Google Scholar 

  60. Muscella AA-O, Stefàno E, Marsigliante S (2020) The effects of exercise training on lipid metabolism and coronary heart disease. Am J Physiol Heart Circ Physiol 319(1):H76–H88. https://doi.org/10.1152/ajpheart.00708.2019

    Article  CAS  PubMed  Google Scholar 

  61. Wenzel SE, Tyurina YY, Zhao J, St Croix CM, Dar HH, Mao G, Tyurin VA et al (2017) PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 171(3):628-641.e26. https://doi.org/10.1016/j.cell.2017.09.044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ivanov I, Heydeck D, Hofheinz K, Roffeis J, O’Donnell VB, Kuhn H, Walther M (2010) Molecular enzymology of lipoxygenases. Arch Biochem Biophys 503(2):161–174. https://doi.org/10.1016/j.abb.2010.08.016

    Article  CAS  PubMed  Google Scholar 

  63. Gao S, Zhou LA-O, Lu J, Fang Y, Wu H, Xu W, Pan Y et al (2022) Cepharanthine attenuates early brain injury after subarachnoid hemorrhage in mice via inhibiting 15-lipoxygenase-1-mediated microglia and endothelial cell ferroptosis. Oxid Med Cell Longev 2022:4295208

    Article  PubMed  PubMed Central  Google Scholar 

  64. Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BA-O (2016) Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA 113(34):E4966–E4975. https://doi.org/10.1073/pnas.1603244113

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  65. Singh NK, Rao GN (2019) Emerging role of 12/15-lipoxygenase (ALOX15) in human pathologies. Prog Lipid Res 73:28–45. https://doi.org/10.1016/j.plipres.2018.11.001

    Article  CAS  PubMed  Google Scholar 

  66. He S, Li R, Peng Y, Wang Z, Huang J, Meng H, Min J et al (2022) ACSL4 contributes to ferroptosis-mediated rhabdomyolysis in exertional heat stroke. J Cachexia Sarcopenia Muscle 13(3):1717–1730. https://doi.org/10.1002/jcsm.12953

    Article  PubMed  PubMed Central  Google Scholar 

  67. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, Irmler MA-OX et al (2017) ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 13(1):91–98. https://doi.org/10.1038/nchembio.2239

    Article  CAS  PubMed  Google Scholar 

  68. Pei Z, Liu Y, Liu S, Jin W, Luo Y, Sun M, Duan Y et al (2021) FUNDC1 insufficiency sensitizes high fat diet intake-induced cardiac remodeling and contractile anomaly through ACSL4-mediated ferroptosis. Metabolism 122:154840. https://doi.org/10.1016/j.metabol.2021.154840

    Article  CAS  PubMed  Google Scholar 

  69. Zhou Y, Zhou H, Hua L, Hou C, Jia Q, Chen J, Zhang S et al (2021) Verification of ferroptosis and pyroptosis and identification of PTGS2 as the hub gene in human coronary artery atherosclerosis. Free Radic Biol Med 171:55–68. https://doi.org/10.1016/j.freeradbiomed.2021.05.009

    Article  CAS  PubMed  Google Scholar 

  70. Askari B, Kanter JE, Sherrid AM, Golej DL, Bender AT, Liu J, Hsueh WA, Beavo JA et al (2007) Rosiglitazone inhibits acyl-CoA synthetase activity and fatty acid partitioning to diacylglycerol and triacylglycerol via a peroxisome proliferator-activated receptor-gamma-independent mechanism in human arterial smooth muscle cells and macrophages. Diabetes 56(4):1143–1152. https://doi.org/10.2337/db06-0267

    Article  CAS  PubMed  Google Scholar 

  71. Liu L, Kang XX (2022) ACSL4 is overexpressed in psoriasis and enhances inflammatory responses by activating ferroptosis. Biochem Biophys Res Commun 623:1–8. https://doi.org/10.1016/j.bbrc.2022.07.041

    Article  CAS  PubMed  Google Scholar 

  72. Quan J, Bode AM, Luo X (2021) ACSL family: the regulatory mechanisms and therapeutic implications in cancer. Eur J Pharmacol 909:174397. https://doi.org/10.1016/j.ejphar.2021.174397

    Article  CAS  PubMed  Google Scholar 

  73. Zhang HL, Hu BX, Li ZL, Du T, Shan JL, Ye ZP, Peng XD et al (2022) PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat Cell Biol 24(1):88–98. https://doi.org/10.1038/s41556-021-00818-3

    Article  CAS  PubMed  Google Scholar 

  74. Yuan Y, Mei Z, Qu Z, Li G, Yu S, Liu Y, Liu K et al (2023) Exosomes secreted from cardiomyocytes suppress the sensitivity of tumor ferroptosis in ischemic heart failure. Signal Transduct Target Ther 8(1):121. https://doi.org/10.1038/s41392-023-01336-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chen YA-O, Li S, Yin M, Li Y, Chen C, Zhang J, Sun K et al (2023) Isorhapontigenin attenuates cardiac microvascular injury in diabetes via the inhibition of mitochondria-associated ferroptosis through PRDX2-MFN2-ACSL4 pathways. Diabetes 72(3):389–404. https://doi.org/10.2337/db22-0553

    Article  CAS  PubMed  Google Scholar 

  76. Chen XA-O, Kang RA-O, Kroemer GA-O, Tang DA-O (2021) Ferroptosis in infection, inflammation, and immunity. J Exp Med 218(6):e20210518. https://doi.org/10.1084/jem.20210518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sun Y, Chen P, Zhai B, Zhang M, Xiang Y, Fang J, Xu S et al (2020) The emerging role of ferroptosis in inflammation. Biomed Pharmacother 127:110108. https://doi.org/10.1016/j.biopha.2020.110108

    Article  CAS  PubMed  Google Scholar 

  78. Kar F, Yıldız F, Hacioglu C, Kar E, Donmez DB, Senturk H, Kanbak G (2023) LoxBlock-1 or curcumin attenuates liver, pancreas and cardiac ferroptosis, oxidative stress and injury in Ischemia/reperfusion-damaged rats by facilitating ACSL/GPx4 signaling. Tissue Cell 82:102114. https://doi.org/10.1016/j.tice.2023.102114

    Article  CAS  PubMed  Google Scholar 

  79. Kim Y, Clifton PA-OX (2018) Curcumin, cardiometabolic health and dementia. Int J Environ Res Public Health 15(10):2093. https://doi.org/10.3390/ijerph15102093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Abrahams S, Haylett WL, Johnson G, Carr JA, Bardien S (2019) Antioxidant effects of curcumin in models of neurodegeneration, aging, oxidative and nitrosative stress: a review. Neuroscience 406:1–21. https://doi.org/10.1016/j.neuroscience.2019.02.020

    Article  CAS  PubMed  Google Scholar 

  81. Yu T, Dohl J, Wang L, Chen Y, Gasier HG, Deuster PA (2020) Curcumin ameliorates heat-induced injury through NADPH oxidase-dependent redox signaling and mitochondrial preservation in C2C12 myoblasts and mouse skeletal muscle. J Nutr 150(9):2257–2267. https://doi.org/10.1093/jn/nxaa201

    Article  PubMed  PubMed Central  Google Scholar 

  82. Kim G, Piao C, Oh J, Lee M (2019) Combined delivery of curcumin and the heme oxygenase-1 gene using cholesterol-conjugated polyamidoamine for anti-inflammatory therapy in acute lung injury. Phytomedicine 56:165–174. https://doi.org/10.1016/j.phymed.2018.09.240

    Article  CAS  PubMed  Google Scholar 

  83. Chen Y, Li C, Duan S, Yuan X, Liang J, Hou S (2019) Curcumin attenuates potassium oxonate-induced hyperuricemia and kidney inflammation in mice. Biomed Pharmacother 118:109195. https://doi.org/10.1016/j.biopha.2019.109195

    Article  CAS  PubMed  Google Scholar 

  84. Li X, Zhu R, Jiang H, Yin Q, Gu J, Chen J, Ji X et al (2022) Autophagy enhanced by curcumin ameliorates inflammation in atherogenesis via the TFEB-P300-BRD4 axis. Acta Pharm Sin B 12(5):2280–2299. https://doi.org/10.1016/j.apsb.2021.12.014

    Article  CAS  PubMed  Google Scholar 

  85. Pivari FA-O, Mingione AA-O, Piazzini G, Ceccarani CA-O, Ottaviano EA-O, Brasacchio C, Dei Cas MA-O et al (2022) Curcumin supplementation (Meriva(®)) modulates inflammation, lipid peroxidation and gut microbiota composition in chronic kidney disease. Nutrients 14(1):231. https://doi.org/10.3390/nu14010231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wang X, Chen X, Zhou W, Men H, Bao T, Sun Y, Wang Q et al (2022) Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways. Acta Pharm Sin B 12(2):708–722. https://doi.org/10.1016/j.apsb.2021.10.005

    Article  CAS  PubMed  Google Scholar 

  87. Zhang Y, Wu Q, Liu J, Zhang Z, Ma X, Zhang Y, Zhu J et al (2022) Sulforaphane alleviates high fat diet-induced insulin resistance via AMPK/Nrf2/GPx4 axis. Biomed Pharmacother 152:113273. https://doi.org/10.1016/j.biopha.2022.113273

    Article  CAS  PubMed  Google Scholar 

  88. Ishida K, Kaji K, Sato S, Ogawa H, Takagi H, Takaya H, Kawaratani H et al (2021) Sulforaphane ameliorates ethanol plus carbon tetrachloride-induced liver fibrosis in mice through the Nrf2-mediated antioxidant response and acetaldehyde metabolization with inhibition of the LPS/TLR4 signaling pathway. J Nutr Biochem 89:108573. https://doi.org/10.1016/j.jnutbio.2020.108573

    Article  CAS  PubMed  Google Scholar 

  89. Li D, Shao R, Wang N, Zhou N, Du K, Shi J, Wang Y et al (2021) Sulforaphane activates a lysosome-dependent transcriptional program to mitigate oxidative stress. Autophagy 17(4):872–887. https://doi.org/10.1080/15548627.2020.1739442

    Article  CAS  PubMed  Google Scholar 

  90. Franke M, Bieber M, Kraft P, Weber ANR, Stoll G, Schuhmann MK (2021) The NLRP3 inflammasome drives inflammation in ischemia/reperfusion injury after transient middle cerebral artery occlusion in mice. Brain Behav Immun 92:223–233. https://doi.org/10.1016/j.bbi.2020.12.009

    Article  CAS  PubMed  Google Scholar 

  91. Vashi R, Patel BA-O (2021) NRF2 in cardiovascular diseases: a ray of hope! J Cardiovasc Transl Res 14(3):573–586. https://doi.org/10.1007/s12265-020-10083-8

    Article  PubMed  Google Scholar 

  92. Dodson M, Castro-Portuguez R, Zhang DD (2019) NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol 23:101107. https://doi.org/10.1016/j.redox.2019.101107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Baird L, Yamamoto M (2020) The molecular mechanisms regulating the KEAP1-NRF2 pathway. Mol Cell Biol 40(13):e00099-20. https://doi.org/10.1128/MCB.00099-20

    Article  PubMed  PubMed Central  Google Scholar 

  94. Bellezza I, Giambanco I, Minelli A, Donato R (2018) Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res 1865(5):721–733. https://doi.org/10.1016/j.bbamcr.2018.02.010

    Article  CAS  PubMed  Google Scholar 

  95. Yuan Y, Zhai Y, Chen J, Xu X, Wang HA-O (2021) Kaempferol ameliorates oxygen-glucose deprivation/reoxygenation-induced neuronal ferroptosis by activating Nrf2/SLC7A11/GPX4 axis. Biomolecules 11(7):923. https://doi.org/10.3390/biom11070923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Dong H, Qiang Z, Chai D, Peng J, Xia Y, Hu R, Jiang H (2020) Nrf2 inhibits ferroptosis and protects against acute lung injury due to intestinal ischemia reperfusion via regulating SLC7A11 and HO-1. Aging (Albany NY) 12(13):12943–12959. https://doi.org/10.18632/aging.103378

    Article  CAS  PubMed  Google Scholar 

  97. Wang Y, Mandal AK, Son YO, Pratheeshkumar P, Wise JTF, Wang L, Zhang Z et al (2018) Roles of ROS, Nrf2, and autophagy in cadmium-carcinogenesis and its prevention by sulforaphane. Toxicol Appl Pharmacol 353:23–30. https://doi.org/10.1016/j.taap.2018.06.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ghafouri-Fard SA-OX, Shoorei HA-O, Bahroudi Z, Hussen BA-O, Talebi SF, Taheri M, Ayatollahi SA (2022) Nrf2-related therapeutic effects of curcumin in different disorders. Biomolecules 12(1):82. https://doi.org/10.3390/biom12010082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bonnefont-Rousselot D (2016) Resveratrol and cardiovascular diseases. Nutrients 8(5):250. https://doi.org/10.3390/nu8050250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yang W, Wang Y, Zhang C, Huang Y, Yu J, Shi L, Zhang P et al (2022) Maresin1 protect against ferroptosis-induced liver injury through ROS inhibition and Nrf2/HO-1/GPX4 activation. Front Pharmacol 13:865689. https://doi.org/10.3389/fphar.2022.865689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Li Y, Xu B, Ren X, Wang L, Xu Y, Zhao Y, Yang C et al (2022) Inhibition of CISD2 promotes ferroptosis through ferritinophagy-mediated ferritin turnover and regulation of p62-Keap1-NRF2 pathway. Cell Mol Biol Lett 27(1):81. https://doi.org/10.1186/s11658-022-00383-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhang Q, Liu J, Duan H, Li R, Peng W, Wu C (2021) Activation of Nrf2/HO-1 signaling: an important molecular mechanism of herbal medicine in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress. J Adv Res 34:43–63. https://doi.org/10.1016/j.jare.2021.06.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Rehman S, Mahboob T, Kamali MF (2022) Correlation between serum malondialdehyde levels and prevalence of cardiovascular disease in haemodialysis treated patients. J Pak Med Assoc 72(8):1557–1580. https://doi.org/10.47391/JPMA.4402

    Article  PubMed  Google Scholar 

  104. Miotto G, Rossetto M, Di Paolo ML, Orian L, Venerando R, Roveri A, Vučković AM et al (2020) Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol 28:101328. https://doi.org/10.1016/j.redox.2019.101328

    Article  CAS  PubMed  Google Scholar 

  105. Ouyang S, Li H, Lou L, Huang Q, Zhang Z, Mo J, Li M et al (2022) Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer. Redox Biol 52:102317. https://doi.org/10.1016/j.redox.2022.102317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Agunbiade TA, Zaghlol RY, Barac A (2019) Heart failure in relation to anthracyclines and other chemotherapies. Methodist DeBakey Cardiovasc J 15(4):243–249. https://doi.org/10.14797/mdcj-15-4-243

    Article  PubMed  PubMed Central  Google Scholar 

  107. Gao W, Wang X, Zhou Y, Wang X, Yu Y (2022) Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy. Signal Transduct Target Ther 7(1):196. https://doi.org/10.1038/s41392-022-01046-3

    Article  PubMed  PubMed Central  Google Scholar 

  108. Chen Z, Yan Y, Qi C, Liu J, Li L, Wang J (2021) The role of ferroptosis in cardiovascular disease and its therapeutic significance. Front Cardiovasc Med 8:733229. https://doi.org/10.3389/fcvm.2021.733229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wang XD, Kang S (2021) Ferroptosis in myocardial infarction: not a marker but a maker. Open Biol 11(4):200367. https://doi.org/10.1098/rsob.200367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Cena H, Calder PC (2020) Defining a healthy diet: evidence for the role of contemporary dietary patterns in health and disease. Nutrients 12(2):334. https://doi.org/10.3390/nu12020334

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the Excellent Youth Project of Hunan Provincial Education Department under Grant No.22B0411.

Author information

Author notes

  1. Qun Zeng and Tingting Jiang contributed equally to this study.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China

    Qun Zeng

  2. The Affiliated Nanhua Hospital, Department of Clinical Laboratory, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China

    Tingting Jiang

Authors
  1. Qun Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tingting Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Qun Zeng: Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data, final approval of the version to be published.  Tingting Jiang: Drafting the article or revising it critically for important intellectual content.

Corresponding author

Correspondence to Qun Zeng.

Ethics declarations

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zeng, Q., Jiang, T. Molecular mechanisms of ferroptosis in cardiovascular disease. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04940-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11010-024-04940-2

Keywords

Search

Navigation