铁死亡的发生机制及其在非酒精性脂肪性肝病/非酒精性脂肪性肝炎发生发展中的作用

刘鸣昊; 刘素彤; 张丽慧; 顾亚娇; 尚东方; 肖准; 赵文霞

doi:10.3969/j.issn.1001-5256.2022.05.037

铁死亡的发生机制及其在非酒精性脂肪性肝病/非酒精性脂肪性肝炎发生发展中的作用

DOI: 10.3969/j.issn.1001-5256.2022.05.037

河南中医药大学第一附属医院脾胃肝胆科，郑州 450000

基金项目:

国家自然科学基金 (81904154);

河南省科技攻关计划 (202102310168);

河南省重点研发与推广专项课题 (192102310425);

河南省中医药科学研究专项课题 (2019JDZX2051);

河南省科技攻关计划项目 (202102310495);

河南省特色骨干学科中医学学科建设项目 (STG-ZYXKY-2020024)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：赵文霞负责拟定题目和文章框架：刘素彤负责撰写论文; 张丽慧、顾亚娇、尚东方、肖准负责修改论文; 刘鸣昊负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
赵文霞，zhao-wenxia@163.com

计量
- 文章访问数: 722
- HTML全文浏览量: 1055
- PDF下载量: 163
- 被引次数: 0
出版历程
- 收稿日期: 2022-01-20
- 出版日期: 2022-05-20

Mechanism of ferroptosis in the formation of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Department of Hepatology and Spleen-Stomach, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China

Research funding:

National Natural Science Foundation of China （81904154）

The Science and Technology Research Program of Henan Province （202102310168）

Key Research and Promotion Project of Henan Province （192102310425）

Traditional Chinese Medicine Science Research Project of Henan Province （2019JDZX2051）

Key Science and Technology Project of Henan Province （202102310495）

TCM Discipline Construction Project of Characteristic Backbone Disciplines of Henan Province （STG-ZYXKY-2020024）

More Information

Corresponding author: ZHAO Wenxia, zhao-wenxia@163.com(ORCID: 0000-0001-6666-9469)

摘要

摘要: 铁死亡是脂质过氧化驱动、铁依赖的细胞死亡。发生机制与铁稳态失衡、脂质过氧化及SLC7A11-GSH-GPX4抗氧化系统有关。在非酒精性脂肪性肝病(NAFLD)/非酒精性脂肪性肝炎(NASH)的发生发展中发挥关键作用。抑制铁死亡，几乎可以完全抑制NASH发生。通过对铁死亡发生机制及其在NAFLD/NASH疾病中的作用和进展进行综述，并提出铁死亡研究的策略和技术手段，以期为NAFLD/NASH机制研究提供参考。
- 非酒精性脂肪性肝病 /
- 铁死亡 /
- 脂质过氧化
Abstract: Ferroptosis is a type of iron-dependent cell death driven by lipid peroxidation, and its mechanism is associated with iron homeostasis imbalance, lipid peroxidation, and slC7A11-GSH-GPX4 antioxidant system. Ferroptosis plays a key role in the development and progression of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), and inhibition of ferroptosis can almost completely inhibit the development of NASH. This article reviews the research advances in the mechanism of ferroptosis and its role in NAFLD/NASH and proposes the research strategies and technical means for ferroptosis, so as to provide a reference for research on the mechanism of NAFLD/NASH.
- Non-alcoholic Fatty Liver Disease /
- Iron Death /
- Lipid Peroxidation

HTML全文

图 1 铁死亡的发生机制

注：a, System Xc—GSH-GPX4轴与铁死亡发生机制; b，脂质过氧化与铁死亡发生机制; c，铁稳态失衡与铁死亡发生机制。NCOA4，自噬特异性识别蛋白核受体辅激活因子4;TCA循环，三羧酸循环; Fe²⁺，二价亚铁离子; Fe³⁺，三价铁离子; GSH，谷胱甘肽; GPX4，谷胱甘肽过氧化酶4。

Figure 1. The mechanism of ferroptosis

下载: 全尺寸图片幻灯片

参考文献(36)

[1]	YOUNOSSI Z, ANSTEE QM, MARIETTI M, et al. Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(1): 11-20. DOI: 10.1038/nrgastro.2017.109.
[2]	MANNE V, HANDA P, KOWDLEY KV. Pathophysiology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis[J]. Clin Liver Dis, 2018, 22(1): 23-37. DOI: 10.1016/j.cld.2017.08.007.
[3]	TSURUSAKI S, TSUCHIYA Y, KOUMURA T, et al. Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis[J]. Cell Death Dis, 2019, 10(6): 449. DOI: 10.1038/s41419-019-1678-y.
[4]	STOCKWELL BR, FRIEDMANN ANGELI JP, BAYIR H, et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease[J]. Cell, 2017, 171(2): 273-285. DOI: 10.1016/j.cell.2017.09.021.
[5]	JHELUM P, SANTOS-NOGUEIRA E, TEO W, et al. Ferroptosis mediates cuprizone-induced loss of oligodendrocytes and demyelination[J]. J Neurosci, 2020, 40(48): 9327-9341. DOI: 10.1523/JNEUROSCI.1749-20.2020.
[6]	REICHERT CO, DE FREITAS FA, SAMPAIO-SILVA J, et al. Ferroptosis mechanisms involved in neurodegenerative diseases[J]. Int J Mol Sci, 2020, 21(22). DOI: 10.3390/ijms21228765.
[7]	HOU W, XIE Y, SONG X, et al. Autophagy promotes ferroptosis by degradation of ferritin[J]. Autophagy, 2016, 12(8): 1425-1428. DOI: 10.1080/15548627.2016.1187366.
[8]	QIAO YX, WANG B, XUE WJ, et al. Advancement of research on ferroptosis in acute kidney injury[J]. Ogran Transplant, 2020, 11(6): 671-676. DOI: 10.3969/j.issn.1674-7445.2020.06.004. 乔予希, 王博, 薛武军, 等. 急性肾损伤过程中铁死亡的研究进展[J]. 器官移植, 2020, 11(6): 671-676. DOI: 10.3969/j.issn.1674-7445.2020.06.004.
[9]	QUILES DEL REY M, MANCIAS JD. NCOA4-mediated ferritinophagy: A potential link to neurodegeneration[J]. Front Neurosci, 2019, 13: 238. DOI: 10.3389/fnins.2019.00238.
[10]	KANG R, ZHU S, ZEH HJ, et al. BECN1 is a new driver of ferroptosis[J]. Autophagy, 2018, 14(12): 2173-2175. DOI: 10.1080/15548627.2018.1513758.
[11]	SONG X, ZHU S, CHEN P, et al. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system X(c)(-) activity[J]. Curr Biol, 2018, 28(15): 2388-2399. e5. DOI: 10.1016/j.cub.2018.05.094.
[12]	LI J, CAO F, YIN HL, et al. Ferroptosis: Past, present and future[J]. Cell Death Dis, 2020, 11(2): 88. DOI: 10.1038/s41419-020-2298-2.
[13]	CHO SH, CHO YJ, PARK JH. The human symbiont Bacteroides thetaiotaomicron promotes diet-induced obesity by regulating host lipid metabolism[J]. J Microbiol, 2022, 60(1): 118-127. DOI: 10.1007/s12275-022-1614-1.
[14]	WEILAND A, WANG Y, WU W, et al. Ferroptosis and its role in diverse brain diseases[J]. Mol Neurobiol, 2019, 56(7): 4880-4893. DOI: 10.1007/s12035-018-1403-3.
[15]	KILLION EA, REEVES AR, EL AZZOUNY MA, et al. A role for long-chain acyl-CoA synthetase-4 (ACSL4) in diet-induced phospholipid remodeling and obesity-associated adipocyte dysfunction[J]. Mol Metab, 2018, 9: 43-56. DOI: 10.1016/j.molmet.2018.01.012.
[16]	DOLL S, PRONETH B, TYURINA YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition[J]. Nat Chem Biol, 2017, 13(1): 91-98. DOI: 10.1038/nchembio.2239.
[17]	DUAN J, WANG Z, DUAN R, et al. Therapeutic targeting of hepatic ACSL4 ameliorates NASH in mice[J]. Hepatology, 2022, 75(1): 140-153. DOI: 10.1002/hep.32148.
[18]	MIKULSKA-RUMINSKA K, ANTHONYMUTHU TS, LEVKINA A, et al. NO^(●) represses the oxygenation of arachidonoyl PE by 15LOX/PEBP1: Mechanism and role in ferroptosis[J]. Int J Mol Sci, 2021, 22(10): 5253. DOI: 10.3390/ijms22105253.
[19]	WU X, LIU C, LI Z, et al. Regulation of GSK3β/Nrf2 signaling pathway modulated erastin-induced ferroptosis in breast cancer[J]. Mol Cell Biochem, 2020, 473(1-2): 217-228. DOI: 10.1007/s11010-020-03821-8.
[20]	ZOU Y, LI H, GRAHAM ET, et al. Author correction: Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis[J]. Nat Chem Biol, 2021, 17(4): 501. DOI: 10.1038/s41589-021-00767-w.
[21]	DIXON SJ, LEMBERG KM, LAMPRECHT MR, et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060-1072. DOI: 10.1016/j.cell.2012.03.042.
[22]	STOCKWELL BR, FRIEDMANN ANGELI JP, BAYIR H, et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease[J]. Cell, 2017, 171(2): 273-285. DOI: 10.1016/j.cell.2017.09.021.
[23]	JHELUM P, SANTOS-NOGUEIRA E, TEO W, et al. Ferroptosis mediates cuprizone-induced loss of oligodendrocytes and demyelination[J]. J Neurosci, 2020, 40(48): 9327-9341. DOI: 10.1523/JNEUROSCI.1749-20.2020.
[24]	REICHERT CO, de FREITAS FA, SAMPAIO-SILVA J, et al. Ferroptosis mechanisms involved in neurodegenerative diseases[J]. Int J Mol Sci, 2020, 21(22): 8756. DOI: 10.3390/ijms21228765.
[25]	HSIEH CH, LIN YJ, CHEN WL, et al. HIF-1α triggers long-lasting glutamate excitotoxicity via system x(c)(-) in cerebral ischaemia-reperfusion[J]. J Pathol, 2017, 241(3): 337-349. DOI: 10.1002/path.4838.
[26]	KOWDLEY KV, BELT P, WILSON LA, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease[J]. Hepatology, 2012, 55(1): 77-85. DOI: 10.1002/hep.24706.
[27]	PIERANTONELLI I, SVEGLIATI-BARONI G. Nonalcoholic fatty liver disease: Basic pathogenetic mechanisms in the progression from NAFLD to NASH[J]. Transplantation, 2019, 103(1): e1-e13. DOI: 10.1097/TP.0000000000002480.
[28]	FENG Y, LI CJ, ZHANG C. Correlation analysis of iron metabolism in patients with nonalcoholic fatty liver disease[J]. J Clin Int Med, 2011, 28(6): 409-411. DOI: 10.3969/j.issn.1001-9057.2011.06.018 冯烨, 李成江, 张楚. 非酒精性脂肪肝病与铁代谢异常的相关性分析[J]. 临床内科杂志, 2011, 28(6): 409-411. DOI: 10.3969/j.issn.1001-9057.2011.06.018
[29]	VIOLI F, CANGEMI R. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis[J]. N Engl J Med, 2010, 363(12): 1185-1186; author reply 1186. DOI: 10.1056/NEJMc1006581.
[30]	YU Y, JIANG L, WANG H, et al. Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis[J]. Blood, 2020, 136(6): 726-739. DOI: 10.1182/blood.2019002907.
[31]	ZHANG FY, ADILA YKP, ZHAO JM, et al. Mechanism of ferroptosis and its role in liver diseases[J]. J Clin Hepatol, 2021, 37(6): 1454-1458. DOI: 10.3969/j.issn.1001-5256.2021.06.049. 张飞宇, 阿迪拉·亚克普, 赵金明, 等. 铁死亡的发生机制及在肝脏疾病中的作用[J]. 临床肝胆病杂志, 2021, 37(6): 1454-1458. DOI: 10.3969/j.issn.1001-5256.2021.06.049.
[32]	TANG D, CHEN X, KANG R, et al. Ferroptosis: Molecular mechanisms and health implications[J]. Cell Res, 2021, 31(2): 107-125. DOI: 10.1038/s41422-020-00441-1.
[33]	MOU Y, WANG J, WU J, et al. Ferroptosis, a new form of cell death: Opportunities and challenges in cancer[J]. J Hematol Oncol, 2019, 12(1): 34. DOI: 10.1186/s13045-019-0720-y.
[34]	LI N, WANG W, ZHOU H, et al. Ferritinophagy-mediated ferroptosis is involved in sepsis-induced cardiac injury[J]. Free Radic Biol Med, 2020, 160: 303-318. DOI: 10.1016/j.freeradbiomed.2020.08.009.
[35]	QI J, KIM JW, ZHOU Z, et al. Ferroptosis affects the progression of nonalcoholic steatohepatitis via the modulation of lipid peroxidation-mediated cell death in mice[J]. Am J Pathol, 2020, 190(1): 68-81. DOI: 10.1016/j.ajpath.2019.09.011.
[36]	TSURUSAKI S, TSUCHIYA Y, KOUMURA T, et al. Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis[J]. Cell Death Dis, 2019, 10(6): 449. DOI: 10.1038/s41419-019-1678-y.