铁死亡调控在肝脏疾病治疗中的研究进展

doi:10.3969/j.issn.1674-8115.2023.03.013

上海交通大学学报（医学版） ›› 2023, Vol. 43 ›› Issue (3): 365-373.doi: 10.3969/j.issn.1674-8115.2023.03.013

铁死亡调控在肝脏疾病治疗中的研究进展

陈晨¹(), 程卓安¹, 王存¹^,², 夏强¹^,²^,³()

^1.上海交通大学医学院附属仁济医院肝脏外科，上海 200120
^2.上海市肿瘤研究所癌基因及相关基因国家重点实验室，上海 200120
^3.上海市器官移植研究所，上海器官移植与免疫工程技术研究中心，上海 200120

收稿日期:2022-07-12 接受日期:2022-12-16 出版日期:2023-03-28 发布日期:2023-03-28
通讯作者: 夏　强，电子信箱：xiaqiang@shsmu.edu.cn。
作者简介:陈　晨（1996—），女，住院医师，博士；电子信箱：18217597089@163.com。
基金资助:
国家自然科学基金(92059205)

Research progress in ferroptosis regulation in the treatment of liver diseases

CHEN Chen¹(), CHENG Zhuoan¹, WANG Cun¹^,², XIA Qiang¹^,²^,³()

^1.Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
^2.State Key Laboratory of Oncogenes and Related Gens, Shanghai Cancer Institute, Shanghai 200120, China
^3.Shanghai Institute of Transplantation, Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200120, China

Received:2022-07-12 Accepted:2022-12-16 Online:2023-03-28 Published:2023-03-28
Contact: XIA Qiang, E-mail: xiaqiang@shsmu.edu.cn.
Supported by:
National Natural Science Foundation of China(92059205)

摘要/Abstract

摘要：

铁死亡是由于脂质活性氧自由基累积造成的细胞死亡，以铁依赖的脂质双分子层氧化性损伤为特征。铁积累和脂质过氧化是铁死亡过程中的关键标志。铁稳态、氧化还原稳态、脂质合成等过程失调可影响铁死亡。目前已报道铁死亡的主要调控轴包括胱氨酸/谷氨酸转运体（System X_c^-）-谷胱甘肽（glutathione，GSH）-谷胱甘肽过氧化物酶4（glutathione peroxidase 4，GPX4）轴、辅酶Q10（coenzyme Q10，CoQ10）-铁死亡抑制蛋白（ferroptosis suppressor protein 1，FSP1）-泛醇轴、GTP环化水解酶1（GTP cyclohydrolase 1，GCH1）-四氢生物蝶呤（tetrahydrobiopterin，BH4）-二氢叶酸还原酶（dihydrofolate reductase，DHFR）-磷脂轴、二氢乳清酸脱氢酶（dehydrogenase，DHODH）-泛醇轴等。铁死亡被视为重要的细胞死亡形式，在肝细胞癌、肝缺血再灌注损伤、脂肪性肝炎、肝纤维化、肝硬化和肝脏代谢病等多种疾病中发挥重要的作用，清晰阐释铁死亡的分子机制可为上述肝脏疾病的治疗提供潜在靶点。因此，该综述主要概括和探讨铁死亡的分子特征、相关生物学过程、调控途径，以及调控铁死亡在肝脏疾病治疗中的研究现状。

关键词: 铁死亡, 肝脏疾病, 脂质过氧化

Abstract:

Ferroptosis is a form of cell death that results from accumulation of lipid reactive oxygen species, marked by iron-dependent oxidative damage of phospholipids. Accumulation of iron and lipid hydroperoxides are hallmarks of ferroptosis. Diverse biological contexts, including iron handling, redox homeostasis, imbalance of lipid synthesis, participate in ferroptosis. Mechanistically, pathways of ferroptosis regulation involving System X_c^--glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, coenzyme Q10 (CoQ10)-ferroptosis suppressor protein 1 (FSP1)-ubiquinol axis, GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4)-dihydrofolate reductase (DHFR) axis, dehydrogenase (DHODH)-ubiquinol axis have been discovered. Ferroptosis has been implicated in multiple liver diseases, such as hepatocellular carcinoma, liver ischemia-reperfusion injury, steatohepatitis, liver fibrosis, cirrhosis and liver metabolic diseases. Elucidating its mechanism offers various tractable nodes for therapeutic intervention. Here, we summarize insights into the molecular characteristics, biological processes, regulatory pathways of ferroptosis and its recent advances in the treatment of liver diseases.

Key words: ferroptosis, liver disease, lipid peroxidation

中图分类号:

R575.5

陈晨, 程卓安, 王存, 夏强. 铁死亡调控在肝脏疾病治疗中的研究进展[J]. 上海交通大学学报（医学版）, 2023, 43(3): 365-373.

CHEN Chen, CHENG Zhuoan, WANG Cun, XIA Qiang. Research progress in ferroptosis regulation in the treatment of liver diseases[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(3): 365-373.

图/表 2

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Inducer	Target	Inhibitor	Target
RSL3, ML162, ML210, FIN56, FINO₂	GPX4	Iron chelator	Iron toxicity
Erastin, erastin analogs, IKE, Sorafenib, Sulfasalazine, PE, glutamate, IFN-γ	System X_c^-	Ferrostatin-1, liprostatin-1, deuterated PUFAs, MUFAs	Lipid peroxidation
FIN56	CoQ10	Vitamin E, α-tocopherol, RTA	Lipid propagation
BSO	Glutamate-cysteine ligase	Thiazolidinediones	ACSL4
Statins	HMG-CoA	Baicalein, Zileuton	Lipoxygenases
Brequinar	DHODH
iFSP1	FSP1
Artemisinins	Ferritinophagy
Methotrexate	Dihydrofolate reductase

Inducer	Target	Inhibitor	Target
RSL3, ML162, ML210, FIN56, FINO₂	GPX4	Iron chelator	Iron toxicity
Erastin, erastin analogs, IKE, Sorafenib, Sulfasalazine, PE, glutamate, IFN-γ	System X_c^-	Ferrostatin-1, liprostatin-1, deuterated PUFAs, MUFAs	Lipid peroxidation
FIN56	CoQ10	Vitamin E, α-tocopherol, RTA	Lipid propagation
BSO	Glutamate-cysteine ligase	Thiazolidinediones	ACSL4
Statins	HMG-CoA	Baicalein, Zileuton	Lipoxygenases
Brequinar	DHODH
iFSP1	FSP1
Artemisinins	Ferritinophagy
Methotrexate	Dihydrofolate reductase

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铁死亡调控在肝脏疾病治疗中的研究进展

Research progress in ferroptosis regulation in the treatment of liver diseases

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