Progress of relationship between ferroptosis and acute liver injury_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

MA Minghe ^1,2 ,  LIU Chuanchuan ^1,3

1. School of Clinical Medicine, Qinghai University, Xining 810001, P. R. China;
2. Department of Critical Care Medicine, Qinghai University Affiliated Hospital, Xining 810001, P, R. China;
3. Laboratory of Echinococcosis, Qinghai University Affiliated Hospital, Xining 810001, P. R. China;

Corresponding author：

LIU Chuanchuan, Email: 18797331470@139.com

Keywords：

ferroptosis; acute liver injury; research progress

DOI：

10.7507/1007-9424.202307059

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the mechanism and research progress of ferroptosis in acute liver injury. Method The domestic and foreign literatures related of ferroptosis and acute liver injury were searched and reviewed. Results Ferroptosis was a newly identified form of iron-dependent cell death. The loss of lipid peroxidation repair activity of glutathione peroxidase 4, the presence of redox active iron and the oxidation of phospholipids containing polyunsaturated fatty acids were considered to be distinctive features of ferroptosis. At present, the research on the regulation of ferroptosis genes involved common liver diseases, including drug-induced liver injury, hepatocellular carcinoma, liver fibrosis, liver ischemia-reperfusion injury, liver failure, nonalcoholic fatty liver and so on. Based on the high correlation between ferroptosis and acute liver injury, chemical therapy targeting ferroptosis could provide individualized treatment for patients with acute liver injury in the future. Conclusions The ferroptosis plays a critical role in governing various cellular processes and downstream effects. Its aberrant expression contributes to the development and advancement of acute liver injury through diverse mechanisms. Thoroughly exploring the involvement of the ferroptosis in acute liver injury is of utmost significance, as it holds the potential to unveil novel therapeutic targets for effective management of acute liver injury.

Citation： MA Minghe, LIU Chuanchuan. Progress of relationship between ferroptosis and acute liver injury. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(12): 1501-1506. doi: 10.7507/1007-9424.202307059 Copy

1.	Chen J, Li X, Ge C, et al. The multifaceted role of ferroptosis in liver disease. Cell Death Differ, 2022, 29(3): 467-480.
2.	Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5): 1060-1072.
3.	张维志, 刘连新. 铁死亡机制在肝细胞癌及其耐药中的研究现状与前景. 中国普外基础与临床杂志, 2022, 29(5): 694-700.
4.	Doll S, Conrad M. Iron and ferroptosis: A still ill-defined liaison. IUBMB Life, 2017, 69(6): 423-434.
5.	Pan Q, Luo Y, Xia Q, et al. Ferroptosis and liver fibrosis. Int J Med Sci, 2021, 18(15): 3361-3366.
6.	Yamada N, Karasawa T, Wakiya T, et al. Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis. Am J Transplant, 2020, 20(6): 1606-1618.
7.	Mazhar M, Din AU, Ali H, et al. Implication of ferroptosis in aging. Cell Death Discov, 2021, 7(1): 149.
8.	Zhou RP, Chen Y, Wei X, et al. Novel insights into ferroptosis: Implications for age-related diseases. Theranostics, 2020, 10(26): 11976-11997.
9.	Chen X, Li J, Kang R, et al. Ferroptosis: machinery and regulation. Autophagy, 2021, 17(9): 2054-2081.
10.	Li J, Cao F, Yin HL, et al. Ferroptosis: past, present and future. Cell Death Dis, 2020, 11(2): 88.
11.	Capelletti MM, Manceau H, Puy H, et al. Ferroptosis in liver diseases: an overview. Int J Mol Sci, 2020, 21(14): 4908.
12.	Bochkov VN, Oskolkova OV, Birukov KG, et al. Generation and biological activities of oxidized phospholipids. Antioxid Redox Signal, 2010, 12(8): 1009-1059.
13.	Ursini F, Maiorino M. Lipid peroxidation and ferroptosis: The role of GSH and GPx4. Free Radic Biol Med, 2020, 152: 175-185.
14.	Yu Y, Jiang L, Wang H, et al. Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis. Blood, 2020, 136(6): 726-739.
15.	Daher R, Manceau H, Karim Z. Iron metabolism and the role of the iron-regulating hormone hepcidin in health and disease. Presse Med, 2017, 46(12 Pt 2): e272-e278. doi: 10.1016/j.lpm.2017.10.006.
16.	He YJ, Liu XY, Xing L, et al. Fenton reaction-independent ferroptosis therapy via glutathione and iron redox couple sequentially triggered lipid peroxide generator. Biomaterials, 2020, 241: 119911.
17.	Magtanong L, Ko PJ, To M, et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem Biol, 2019, 26(3): 420-432.
18.	Zeng F, Lan Y, Wang N, et al. Ferroptosis: A new therapeutic target for bladder cancer. Front Pharmacol, 2022, 13: 1043283.
19.	Conrad M, Pratt DA. The chemical basis of ferroptosis. Nat Chem Biol, 2019, 15(12): 1137-1147.
20.	周伟, 吴河水. 铁死亡机制在胰腺癌中的研究现状及未来展望. 中国普外基础与临床杂志, 2023, 30(3): 364-368.
21.	Zhu T, Shi L, Yu C, et al. Ferroptosis promotes photodynamic therapy: supramolecular photosensitizer-inducer nanodrug for enhanced cancer treatment. Theranostics, 2019, 9(11): 3293-3307.
22.	Gracia-Sancho J, Casillas-Ramírez A, Peralta C. Molecular pathways in protecting the liver from ischaemia/reperfusion injury: a 2015 update. Clin Sci (Lond), 2015, 129(4): 345-362.
23.	Friedmann Angeli JP, Schneider M, Proneth B, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol, 2014, 16(12): 1180-1191.
24.	Fang X, Wang H, Han D, et al. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci U S A, 2019, 116(7): 2672-2680.
25.	Li Y, Feng D, Wang Z, et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ, 2019, 26(11): 2284-2299.
26.	Wu Y, Jiao H, Yue Y, et al. Ubiquitin ligase E3 HUWE1/MULE targets transferrin receptor for degradation and suppresses ferroptosis in acute liver injury. Cell Death Differ, 2022, 29(9): 1705-1718.
27.	Levy MM, Dellinger RP, Townsend SR, et al. The Surviving sepsis campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med, 2010, 38(2): 367-374.
28.	Kallinen O, Maisniemi K, Böhling T, et al. Multiple organ failure as a cause of death in patients with severe burns. J Burn Care Res, 2012, 33(2): 206-211.
29.	Kramer L, Jordan B, Druml W, et al. Incidence and prognosis of early hepatic dysfunction in critically ill patients—a prospective multicenter study. Crit Care Med, 2007, 35(4): 1099-1104.
30.	Hall MJ, Levant S, DeFrances CJ. Trends in inpatient hospital deaths: national hospital discharge survey, 2000–2010. NCHS Data Brief, 2013, 118: 1-8.
31.	Mancias JD, Wang X, Gygi SP, et al. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature, 2014, 509(7498): 105-109.
32.	Li Q, Han X, Lan X, et al. Inhibition of neuronal ferroptosis protects hemorrhagic brain. JCI Insight, 2017, 2(7): e90777.
33.	Li N, Wang W, Zhou H, et al. Ferritinophagy-mediated ferroptosis is involved in sepsis-induced cardiac injury. Free Radic Biol Med, 2020, 160: 303-318.
34.	Wang C, Yuan W, Hu A, et al. Dexmedetomidine alleviated sepsis-induced myocardial ferroptosis and septic heart injury. Mol Med Rep, 2020, 22(1): 175-184.
35.	Wang J, Zhu Q, Li R, et al. YAP1 protects against septic liver injury via ferroptosis resistance. Cell Biosci, 2022, 12(1): 163.
36.	Andrade RJ, Chalasani N, Björnsson ES, et al. Drug-induced liver injury. Nat Rev Dis Primers, 2019, 5(1): 58.
37.	Kullak-Ublick GA, Andrade RJ, Merz M, et al. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut, 2017, 66(6): 1154-1164.
38.	Ettel M, Gonzalez GA, Gera S, et al. Frequency and pathological characteristics of drug-induced liver injury in a tertiary medical center. Hum Pathol, 2017, 68: 92-98.
39.	Jaeschke H, Xie Y, McGill MR. Acetaminophen-induced liver injury: from animal models to humans. J Clin Transl Hepatol, 2014, 2(3): 153-161.
40.	Ding CH, Zhu H. Isatidis folium alleviates acetaminophen-induced liver injury in mice by enhancing the endogenous antioxidant system. Environ Toxicol, 2020, 35(11): 1251-1259.
41.	Yamada N, Karasawa T, Kimura H, et al. Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure. Cell Death Dis, 2020, 11(2): 144.
42.	Yan B, Ai Y, Sun Q, et al. Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol Cell, 2021, 81(2): 355-369.
43.	Nagra N, Kozarek RA, Burman BE. Therapeutic advances in viral hepatitis A-E. Adv Ther, 2022, 39(4): 1524-1552.
44.	Kan X, Yin Y, Song C, et al. Newcastle-disease-virus-induced ferroptosis through nutrient deprivation and ferritinophagy in tumor cells. iScience, 2021, 24(8): 102837.
45.	Girelli D, Pasino M, Goodnough JB, et al. Reduced serum hepcidin levels in patients with chronic hepatitis C. J Hepatol, 2009, 51(5): 845-852.
46.	Fujita N, Sugimoto R, Takeo M, et al. Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med, 2007, 13(1-2): 97-104.
47.	Armitage AE, Stacey AR, Giannoulatou E, et al. Distinct patterns of hepcidin and iron regulation during HIV-1, HBV, and HCV infections. Proc Natl Acad Sci U S A, 2014, 111(33): 12187-12192.
48.	Fujita N, Takei Y. Iron, hepatitis C virus, and hepatocellular carcinoma: iron reduction preaches the gospel for chronic hepatitis C. J Gastroenterol, 2007, 42(11): 923-926.
49.	Martin DN, Uprichard SL. Identification of transferrin receptor 1 as a hepatitis C virus entry factor. Proc Natl Acad Sci U S A, 2013, 110(26): 10777-10782.
50.	Gao M, Yi J, Zhu J, et al. Role of Mitochondria in ferroptosis. Mol Cell, 2019, 73(2): 354-363.
51.	Zou DM, Sun WL. Relationship between Hepatitis C virus infection and iron overload. Chin Med J (Engl), 2017, 130(7): 866-871.
52.	Li W, Urban S. Entry of hepatitis B and hepatitis D virus into hepatocytes: Basic insights and clinical implications. J Hepatol, 2016, 64(1 Suppl): S32-S40. doi: 10.1016/j.jhep.2016.02.011.
53.	Czaja AJ. Diagnosis and Management of autoimmune hepatitis: current status and future directions. Gut Liver, 2016, 10(2): 177-203.
54.	Deng G, Li Y, Ma S, et al. Caveolin-1 dictates ferroptosis in the execution of acute immune-mediated hepatic damage by attenuating nitrogen stress. Free Radic Biol Med, 2020, 148: 151-161.
55.	Zeng T, Deng G, Zhong W, et al. Indoleamine 2, 3-dioxygenase 1enhanceshepatocytes ferroptosis in acute immune hepatitis associated with excess nitrative stress. Free Radic Biol Med, 2020, 152: 668-679.
56.	Shojaie L, Iorga A, Dara L. Cell death in liver diseases: a review. Int J Mol Sci, 2020, 21(24): 9682.
57.	Bekric D, Ocker M, Mayr C, et al. Ferroptosis in hepatocellular carcinoma: mechanisms, drug targets and approaches to clinical translation. Cancers (Basel), 2022, 14(7): 1826.
58.	Angeli JPF, Shah R, Pratt DA, et al. Ferroptosis inhibition: mechanisms and opportunities. Trends Pharmacol Sci, 2017, 38(5): 489-498.

1. Chen J, Li X, Ge C, et al. The multifaceted role of ferroptosis in liver disease. Cell Death Differ, 2022, 29(3): 467-480.
2. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5): 1060-1072.
3. 张维志, 刘连新. 铁死亡机制在肝细胞癌及其耐药中的研究现状与前景. 中国普外基础与临床杂志, 2022, 29(5): 694-700.
4. Doll S, Conrad M. Iron and ferroptosis: A still ill-defined liaison. IUBMB Life, 2017, 69(6): 423-434.
5. Pan Q, Luo Y, Xia Q, et al. Ferroptosis and liver fibrosis. Int J Med Sci, 2021, 18(15): 3361-3366.
6. Yamada N, Karasawa T, Wakiya T, et al. Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis. Am J Transplant, 2020, 20(6): 1606-1618.
7. Mazhar M, Din AU, Ali H, et al. Implication of ferroptosis in aging. Cell Death Discov, 2021, 7(1): 149.
8. Zhou RP, Chen Y, Wei X, et al. Novel insights into ferroptosis: Implications for age-related diseases. Theranostics, 2020, 10(26): 11976-11997.
9. Chen X, Li J, Kang R, et al. Ferroptosis: machinery and regulation. Autophagy, 2021, 17(9): 2054-2081.
10. Li J, Cao F, Yin HL, et al. Ferroptosis: past, present and future. Cell Death Dis, 2020, 11(2): 88.
11. Capelletti MM, Manceau H, Puy H, et al. Ferroptosis in liver diseases: an overview. Int J Mol Sci, 2020, 21(14): 4908.
12. Bochkov VN, Oskolkova OV, Birukov KG, et al. Generation and biological activities of oxidized phospholipids. Antioxid Redox Signal, 2010, 12(8): 1009-1059.
13. Ursini F, Maiorino M. Lipid peroxidation and ferroptosis: The role of GSH and GPx4. Free Radic Biol Med, 2020, 152: 175-185.
14. Yu Y, Jiang L, Wang H, et al. Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis. Blood, 2020, 136(6): 726-739.
15. Daher R, Manceau H, Karim Z. Iron metabolism and the role of the iron-regulating hormone hepcidin in health and disease. Presse Med, 2017, 46(12 Pt 2): e272-e278. doi: 10.1016/j.lpm.2017.10.006.
16. He YJ, Liu XY, Xing L, et al. Fenton reaction-independent ferroptosis therapy via glutathione and iron redox couple sequentially triggered lipid peroxide generator. Biomaterials, 2020, 241: 119911.
17. Magtanong L, Ko PJ, To M, et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem Biol, 2019, 26(3): 420-432.
18. Zeng F, Lan Y, Wang N, et al. Ferroptosis: A new therapeutic target for bladder cancer. Front Pharmacol, 2022, 13: 1043283.
19. Conrad M, Pratt DA. The chemical basis of ferroptosis. Nat Chem Biol, 2019, 15(12): 1137-1147.
20. 周伟, 吴河水. 铁死亡机制在胰腺癌中的研究现状及未来展望. 中国普外基础与临床杂志, 2023, 30(3): 364-368.
21. Zhu T, Shi L, Yu C, et al. Ferroptosis promotes photodynamic therapy: supramolecular photosensitizer-inducer nanodrug for enhanced cancer treatment. Theranostics, 2019, 9(11): 3293-3307.
22. Gracia-Sancho J, Casillas-Ramírez A, Peralta C. Molecular pathways in protecting the liver from ischaemia/reperfusion injury: a 2015 update. Clin Sci (Lond), 2015, 129(4): 345-362.
23. Friedmann Angeli JP, Schneider M, Proneth B, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol, 2014, 16(12): 1180-1191.
24. Fang X, Wang H, Han D, et al. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci U S A, 2019, 116(7): 2672-2680.
25. Li Y, Feng D, Wang Z, et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ, 2019, 26(11): 2284-2299.
26. Wu Y, Jiao H, Yue Y, et al. Ubiquitin ligase E3 HUWE1/MULE targets transferrin receptor for degradation and suppresses ferroptosis in acute liver injury. Cell Death Differ, 2022, 29(9): 1705-1718.
27. Levy MM, Dellinger RP, Townsend SR, et al. The Surviving sepsis campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med, 2010, 38(2): 367-374.
28. Kallinen O, Maisniemi K, Böhling T, et al. Multiple organ failure as a cause of death in patients with severe burns. J Burn Care Res, 2012, 33(2): 206-211.
29. Kramer L, Jordan B, Druml W, et al. Incidence and prognosis of early hepatic dysfunction in critically ill patients—a prospective multicenter study. Crit Care Med, 2007, 35(4): 1099-1104.
30. Hall MJ, Levant S, DeFrances CJ. Trends in inpatient hospital deaths: national hospital discharge survey, 2000–2010. NCHS Data Brief, 2013, 118: 1-8.
31. Mancias JD, Wang X, Gygi SP, et al. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature, 2014, 509(7498): 105-109.
32. Li Q, Han X, Lan X, et al. Inhibition of neuronal ferroptosis protects hemorrhagic brain. JCI Insight, 2017, 2(7): e90777.
33. Li N, Wang W, Zhou H, et al. Ferritinophagy-mediated ferroptosis is involved in sepsis-induced cardiac injury. Free Radic Biol Med, 2020, 160: 303-318.
34. Wang C, Yuan W, Hu A, et al. Dexmedetomidine alleviated sepsis-induced myocardial ferroptosis and septic heart injury. Mol Med Rep, 2020, 22(1): 175-184.
35. Wang J, Zhu Q, Li R, et al. YAP1 protects against septic liver injury via ferroptosis resistance. Cell Biosci, 2022, 12(1): 163.
36. Andrade RJ, Chalasani N, Björnsson ES, et al. Drug-induced liver injury. Nat Rev Dis Primers, 2019, 5(1): 58.
37. Kullak-Ublick GA, Andrade RJ, Merz M, et al. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut, 2017, 66(6): 1154-1164.
38. Ettel M, Gonzalez GA, Gera S, et al. Frequency and pathological characteristics of drug-induced liver injury in a tertiary medical center. Hum Pathol, 2017, 68: 92-98.
39. Jaeschke H, Xie Y, McGill MR. Acetaminophen-induced liver injury: from animal models to humans. J Clin Transl Hepatol, 2014, 2(3): 153-161.
40. Ding CH, Zhu H. Isatidis folium alleviates acetaminophen-induced liver injury in mice by enhancing the endogenous antioxidant system. Environ Toxicol, 2020, 35(11): 1251-1259.
41. Yamada N, Karasawa T, Kimura H, et al. Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure. Cell Death Dis, 2020, 11(2): 144.
42. Yan B, Ai Y, Sun Q, et al. Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol Cell, 2021, 81(2): 355-369.
43. Nagra N, Kozarek RA, Burman BE. Therapeutic advances in viral hepatitis A-E. Adv Ther, 2022, 39(4): 1524-1552.
44. Kan X, Yin Y, Song C, et al. Newcastle-disease-virus-induced ferroptosis through nutrient deprivation and ferritinophagy in tumor cells. iScience, 2021, 24(8): 102837.
45. Girelli D, Pasino M, Goodnough JB, et al. Reduced serum hepcidin levels in patients with chronic hepatitis C. J Hepatol, 2009, 51(5): 845-852.
46. Fujita N, Sugimoto R, Takeo M, et al. Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med, 2007, 13(1-2): 97-104.
47. Armitage AE, Stacey AR, Giannoulatou E, et al. Distinct patterns of hepcidin and iron regulation during HIV-1, HBV, and HCV infections. Proc Natl Acad Sci U S A, 2014, 111(33): 12187-12192.
48. Fujita N, Takei Y. Iron, hepatitis C virus, and hepatocellular carcinoma: iron reduction preaches the gospel for chronic hepatitis C. J Gastroenterol, 2007, 42(11): 923-926.
49. Martin DN, Uprichard SL. Identification of transferrin receptor 1 as a hepatitis C virus entry factor. Proc Natl Acad Sci U S A, 2013, 110(26): 10777-10782.
50. Gao M, Yi J, Zhu J, et al. Role of Mitochondria in ferroptosis. Mol Cell, 2019, 73(2): 354-363.
51. Zou DM, Sun WL. Relationship between Hepatitis C virus infection and iron overload. Chin Med J (Engl), 2017, 130(7): 866-871.
52. Li W, Urban S. Entry of hepatitis B and hepatitis D virus into hepatocytes: Basic insights and clinical implications. J Hepatol, 2016, 64(1 Suppl): S32-S40. doi: 10.1016/j.jhep.2016.02.011.
53. Czaja AJ. Diagnosis and Management of autoimmune hepatitis: current status and future directions. Gut Liver, 2016, 10(2): 177-203.
54. Deng G, Li Y, Ma S, et al. Caveolin-1 dictates ferroptosis in the execution of acute immune-mediated hepatic damage by attenuating nitrogen stress. Free Radic Biol Med, 2020, 148: 151-161.
55. Zeng T, Deng G, Zhong W, et al. Indoleamine 2, 3-dioxygenase 1enhanceshepatocytes ferroptosis in acute immune hepatitis associated with excess nitrative stress. Free Radic Biol Med, 2020, 152: 668-679.
56. Shojaie L, Iorga A, Dara L. Cell death in liver diseases: a review. Int J Mol Sci, 2020, 21(24): 9682.
57. Bekric D, Ocker M, Mayr C, et al. Ferroptosis in hepatocellular carcinoma: mechanisms, drug targets and approaches to clinical translation. Cancers (Basel), 2022, 14(7): 1826.
58. Angeli JPF, Shah R, Pratt DA, et al. Ferroptosis inhibition: mechanisms and opportunities. Trends Pharmacol Sci, 2017, 38(5): 489-498.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Progress of relationship between ferroptosis and acute liver injury

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