铁死亡抑制蛋白1在肝脏疾病中的作用机制及潜在治疗靶点

王思思; 王亚茹; 刘睿; 秦洁

doi:10.12449/JCH240731

铁死亡抑制蛋白1在肝脏疾病中的作用机制及潜在治疗靶点

DOI: 10.12449/JCH240731

山西医科大学附属山西省人民医院内分泌科，太原 030012

基金项目:

山西省自然科学研究面上项目 (202203021211059)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：王思思负责设计论文框架，起草论文；王亚茹、刘睿负责论文修改；秦洁负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
秦洁， hopejieqin@sohu.com （ORCID： 0000-0002-7249-093X）

计量
- 文章访问数: 537
- HTML全文浏览量: 75
- PDF下载量: 31
- 被引次数: 0
出版历程
- 收稿日期: 2023-12-02
- 录用日期: 2024-01-29
- 出版日期: 2024-07-25

Mechanism of action and potential therapeutic targets of ferroptosis suppressor protein 1 in liver diseases

Department of Endocrinology，Shanxi Provincial People’s Hospital，Shanxi Medical University，Taiyuan 030012，China

Research funding:

Natural Science Research General Project of Shanxi Province (202203021211059)

More Information

Corresponding author: QIN Jie， hopejieqin@sohu.com （ORCID： 0000-0002-7249-093X）

摘要

摘要: 铁死亡抑制蛋白1（FSP1）是最近发现除谷胱甘肽过氧化酶4之外的另一个主要的铁死亡调节因子，能够清除细胞内的活性氧和脂质自由基，抑制铁死亡的发生。鉴于肝脏在铁和脂质代谢中的关键作用及其对氧化损伤的易感性，越来越多的证据表明FSP1在代谢相关脂肪性肝病、肝细胞癌、急性肝衰竭、酒精性肝损伤等肝脏疾病中发挥重要作用，FSP1相关靶点有望成为一种潜在的治疗选择。本文旨在对FSP1进行全面综述，重点总结FSP1在几种常见肝病的病理生理学中的作用，强调其作为肝脏疾病靶点的潜力，为肝脏疾病的治疗提供新思路。
- 肝疾病 /
- 抑制蛋白类 /
- 铁死亡
Abstract: Ferroptosis suppressor protein 1 （FSP1） is another major ferroptosis regulator besides glutathione peroxidase 4， which can scavenge intracellular reactive oxygen species and lipid peroxides and inhibit ferroptosis. In view of the key role of the liver in iron and lipid metabolism and its susceptibility to oxidative damage， more and more evidence has shown that FSP1 plays an important role in liver diseases such as metabolic associated fatty liver disease， hepatocellular carcinoma， acute liver failure， and alcoholic liver disease， and the related targets of FSP1 are expected to become a potential treatment option. This article comprehensively reviews FSP1， with a focus on the role of FSP1 in the pathophysiology of several common liver diseases and the potential of FSP1 as a target of liver diseases， in order to provide new ideas for the treatment of liver diseases.
- Liver Diseases /
- Arrestins /
- Ferroptosis

HTML全文

参考文献(40)

[1]	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.
[2]	YANG WS, SRIRAMARATNAM R, WELSCH ME, et al. Regulation of ferroptotic cancer cell death by GPX4[J]. Cell, 2014, 156( 1-2): 317- 331. DOI: 10.1016/j.cell.2013.12.010.
[3]	BERSUKER K, HENDRICKS JM, LI ZP, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis[J]. Nature, 2019, 575( 7784): 688- 692. DOI: 10.1038/s41586-019-1705-2.
[4]	DOLL S, FREITAS FP, SHAH R, et al. FSP1 is a glutathione-independent ferroptosis suppressor[J]. Nature, 2019, 575( 7784): 693- 698. DOI: 10.1038/s41586-019-1707-0.
[5]	MAO C, LIU XG, ZHANG YL, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer[J]. Nature, 2021, 593( 7860): 586- 590. DOI: 10.1038/s41586-021-03539-7.
[6]	KRAFT VAN, BEZJIAN CT, PFEIFFER S, et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling[J]. ACS Cent Sci, 2020, 6( 1): 41- 53. DOI: 10.1021/acscentsci.9b01063.
[7]	ZHENG JS, CONRAD M. The metabolic underpinnings of ferroptosis[J]. Cell Metab, 2020, 32( 6): 920- 937. DOI: 10.1016/j.cmet.2020.10.011.
[8]	KNIGHT TR, FARISS MW, FARHOOD A, et al. Role of lipid peroxidation as a mechanism of liver injury after acetaminophen overdose in mice[J]. Toxicol Sci, 2003, 76( 1): 229- 236. DOI: 10.1093/toxsci/kfg220.
[9]	OHIRO Y, GARKAVTSEV I, KOBAYASHI S, et al. A novel p53-inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis-inducing factor(AIF)[J]. FEBS Lett, 2002, 524( 1-3): 163- 171. DOI: 10.1016/s0014-5793(02)03049-1.
[10]	WU M, XU LG, LI XY, et al. AMID, an apoptosis-inducing factor-homologous mitochondrion-associated protein, induces caspase-independent apoptosis[J]. J Biol Chem, 2002, 277( 28): 25617- 25623. DOI: 10.1074/jbc.M202285200.
[11]	NOVO N, FERREIRA P, MEDINA M. The apoptosis-inducing factor family: Moonlighting proteins in the crosstalk between mitochondria and nuclei[J]. IUBMB Life, 2021, 73( 3): 568- 581. DOI: 10.1002/iub.2390.
[12]	MARSHALL KR, GONG M, WODKE L, et al. The human apoptosis-inducing protein AMID is an oxidoreductase with a modified flavin cofactor and DNA binding activity[J]. J Biol Chem, 2005, 280( 35): 30735- 30740. DOI: 10.1074/jbc.M414018200.
[13]	NGUYEN HP, YI D, LIN F, et al. Aifm2, a NADH oxidase, supports robust glycolysis and is required for cold- and diet-induced thermogenesis[J]. Mol Cell, 2020, 77( 3): 600- 617. DOI: 10.1016/j.molcel.2019.12.002.
[14]	ZENG FR, CHEN X, DENG GT. The anti-ferroptotic role of FSP1: Current molecular mechanism and therapeutic approach[J]. Mol Biomed, 2022, 3( 1): 37. DOI: 10.1186/s43556-022-00105-z.
[15]	MISHIMA E, ITO J, WU ZJ, et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor[J]. Nature, 2022, 608( 7924): 778- 783. DOI: 10.1038/s41586-022-05022-3.
[16]	MLADĚNKA P, MACÁKOVÁ K, KUJOVSKÁ KRČMOVÁ L, et al. Vitamin K-sources, physiological role, kinetics, deficiency, detection, therapeutic use, and toxicity[J]. Nutr Rev, 2022, 80( 4): 677- 698. DOI: 10.1093/nutrit/nuab061.
[17]	YOSHIOKA H, KAWAMURA T, MUROI M, et al. Identification of a small molecule that enhances ferroptosis via inhibition of ferroptosis suppressor protein 1(FSP1)[J]. ACS Chem Biol, 2022, 17( 2): 483- 491. DOI: 10.1021/acschembio.2c00028.
[18]	YOUNOSSI ZM, GOLABI P, PAIK JM, et al. The global epidemiology of nonalcoholic fatty liver disease(NAFLD) and nonalcoholic steatohepatitis(NASH): A systematic review[J]. Hepatology, 2023, 77( 4): 1335- 1347. DOI: 10.1097/HEP.0000000000000004.
[19]	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.
[20]	CRISMAN E, DUARTE P, DAUDEN E, et al. KEAP1-NRF2 protein-protein interaction inhibitors: Design, pharmacological properties and therapeutic potential[J]. Med Res Rev, 2023, 43( 1): 237- 287. DOI: 10.1002/med.21925.
[21]	SLOCUM SL, SKOKO JJ, WAKABAYASHI N, et al. Keap1/Nrf2 pathway activation leads to a repressed hepatic gluconeogenic and lipogenic program in mice on a high-fat diet[J]. Arch Biochem Biophys, 2016, 591: 57- 65. DOI: 10.1016/j.abb.2015.11.040.
[22]	GAO G, XIE ZS, LI EW, et al. Dehydroabietic acid improves nonalcoholic fatty liver disease through activating the Keap1/Nrf2-ARE signaling pathway to reduce ferroptosis[J]. J Nat Med, 2021, 75( 3): 540- 552. DOI: 10.1007/s11418-021-01491-4.
[23]	VENKATESH D, O’BRIEN NA, ZANDKARIMI F, et al. MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling[J]. Genes Dev, 2020, 34( 7-8): 526- 543. DOI: 10.1101/gad.334219.119.
[24]	KANE RC, FARRELL AT, MADABUSHI R, et al. Sorafenib for the treatment of unresectable hepatocellular carcinoma[J]. Oncologist, 2009, 14( 1): 95- 100. DOI: 10.1634/theoncologist.2008-0185.
[25]	DOU T, ZHU XG, YANG H. Research progress on ferroptosis in hepatocellular carcinoma[J/CD]. Chin J Liver Dis Electron Version, 2023, 15( 4): 6- 10. DOI: 10.3969/j.issn.1674-7380.2023.04.002. 窦婷, 朱向高, 杨昊. 铁死亡在肝细胞癌中的研究进展[J/CD]. 中国肝脏病杂志(电子版), 2023, 15( 4): 6- 10. DOI: 10.3969/j.issn.1674-7380.2023.04.002.
[26]	SUN XF, OU ZH, CHEN RC, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells[J]. Hepatology, 2016, 63( 1): 173- 184. DOI: 10.1002/hep.28251.
[27]	LIU MR, SHI C, SONG QY, et al. Sorafenib induces ferroptosis by promoting TRIM54-mediated FSP1 ubiquitination and degradation in hepatocellular carcinoma[J]. Hepatol Commun, 2023, 7( 10): e0246. DOI: 10.1097/HC9.0000000000000246.
[28]	YUAN JS, LV T, YANG J, et al. HDLBP-stabilized lncFAL inhibits ferroptosis vulnerability by diminishing Trim69-dependent FSP1 degradation in hepatocellular carcinoma[J]. Redox Biol, 2022, 58: 102546. DOI: 10.1016/j.redox.2022.102546.
[29]	CHEU JW, LEE D, LI QD, et al. Ferroptosis suppressor protein 1 inhibition promotes tumor ferroptosis and anti-tumor immune responses in liver cancer[J]. Cell Mol Gastroenterol Hepatol, 2023, 16( 1): 133- 159. DOI: 10.1016/j.jcmgh.2023.03.001.
[30]	XAVIER DA SILVA TN, SCHULTE C, ALVES AN, et al. Molecular characterization of AIFM2/FSP1 inhibition by iFSP1-like molecules[J]. Cell Death Dis, 2023, 14( 4): 281. DOI: 10.1038/s41419-023-05787-z.
[31]	NAKAMURA T, HIPP C, SANTOS DIAS MOURÃO A, et al. Phase separation of FSP1 promotes ferroptosis[J]. Nature, 2023, 619( 7969): 371- 377. DOI: 10.1038/s41586-023-06255-6.
[32]	YANG J, JIA ZG, ZHANG J, et al. Metabolic intervention nanoparticles for triple-negative breast cancer therapy via overcoming FSP1-mediated ferroptosis resistance[J]. Adv Healthc Mater, 2022, 11( 13): e2102799. DOI: 10.1002/adhm.202102799.
[33]	HUANG S, WANG YH, XIE SW, et al. Hepatic TGFβr1 deficiency attenuates lipopolysaccharide/D-galactosamine-induced acute liver failure through inhibiting GSK3β-Nrf2-mediated hepatocyte apoptosis and ferroptosis[J]. Cell Mol Gastroenterol Hepatol, 2022, 13( 6): 1649- 1672. DOI: 10.1016/j.jcmgh.2022.02.009.
[34]	OYEWOLE AO, BIRCH-MACHIN MA. Mitochondria-targeted antioxidants[J]. FASEB J, 2015, 29( 12): 4766- 4771. DOI: 10.1096/fj.15-275404.
[35]	HE X, LIANG SM, WANG HQ, et al. Mitoquinone protects against acetaminophen-induced liver injury in an FSP1-dependent and GPX4-independent manner[J]. Toxicol Appl Pharmacol, 2023, 465: 116452. DOI: 10.1016/j.taap.2023.116452.
[36]	JAESCHKE H, RAMACHANDRAN A, CHAO XJ, et al. Emerging and established modes of cell death during acetaminophen-induced liver injury[J]. Arch Toxicol, 2019, 93( 12): 3491- 3502. DOI: 10.1007/s00204-019-02597-1.
[37]	LIU CY, WANG M, YU HM, et al. Ferroptosis is involved in alcohol-induced cell death invivo and invivo[J]. Biosci Biotechnol Biochem, 2020, 84( 8): 1621- 1628. DOI: 10.1080/09168451.2020.1763155.
[38]	LI Y, YANG S. Progress on alcoholic liver disease[J/CD]. Chin J Liver Dis Electron Version, 2022, 14( 3): 1- 4. DOI: 10.3969/j.issn.1674-7380.2022.03.001. 李玥, 杨松. 酒精性肝病研究进展[J/CD]. 中国肝脏病杂志(电子版), 2022, 14( 3): 1- 4. DOI: 10.3969/j.issn.1674-7380.2022.03.001..
[39]	ZHANG Y, ZHAO S, FU Y, et al. Computational repositioning of dimethyl fumarate for treating alcoholic liver disease[J]. Cell Death Dis, 2020, 11( 8): 641. DOI: 10.1038/s41419-020-02890-3.
[40]	WARD NP, DENICOLA GM. Long-sought mediator of vitamin K recycling discovered[J]. Nature, 2022, 608( 7924): 673- 674. DOI: 10.1038/d41586-022-02001-6.