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J Zhejiang Univ (Med Sci)  2020, Vol. 49 Issue (1): 44-57    DOI: 10.3785/j.issn.1008-9292.2020.02.24
    
The role of ferroptosis in chronic diseases
CHEN Junyi(),YANG Xiang,FANG Xuexian,WANG Fudi,MIN Junxia*()
School of Medicine, Zhejiang University, Hangzhou 310058, China
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Abstract  

Recently, ferroptosis, an iron-dependent novel type of cell death, has been characterized as an excessive accumulation of lipid peroxides and reactive oxygen species. Emerging studies demonstrate that ferroptosis not only plays an important role in the pathogenesis and progression of chronic diseases, but also functions differently in the different disease context. Notably, it is shown that activation of ferroptosis could potently inhibit tumor growth and increase sensitivity to chemotherapy and immunotherapy in various cancer settings. As a result, the development of more efficacious ferroptosis agonists remains the mainstay of ferroptosis-targeting strategy for cancer therapeutics. By contrast, in non-cancerous chronic diseases, including cardiovascular & cerebrovascular diseases and neurodegenerative diseases, ferroptosis functions as a risk factor to promote these diseases progression through triggering or accelerating tissue injury. As a matter of fact, blocking ferroptosis has been demonstrated to effectively prevent ischemia-reperfusion heart disease in preclinical animal models. Therefore, it is a promising field to develope potent ferroptosis inhibitors for preventing and treating cardiovascular & cerebrovascular diseases and neurodegenerative diseases. In this article, we summarize the most recent progress on ferroptosis in chronic diseases, and draw attention to the possible clinical impact of this recently emerged ferroptosis modalities.



Key wordsIron metabolism disorder      Ferroptosis      Neoplasms      Neurodegeneration      Vascular diseases      Review     
Received: 18 November 2019      Published: 08 June 2020
CLC:  R364  
Corresponding Authors: MIN Junxia     E-mail: junyichen@zju.edu.cn;junxiamin@zju.edu.cn
Cite this article:

CHEN Junyi,YANG Xiang,FANG Xuexian,WANG Fudi,MIN Junxia. The role of ferroptosis in chronic diseases. J Zhejiang Univ (Med Sci), 2020, 49(1): 44-57.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2020.02.24     OR     http://www.zjujournals.com/med/Y2020/V49/I1/44


铁死亡与重大慢性疾病

铁死亡是近年发现的一种铁依赖的新型细胞死亡方式,其特征是脂质过氧化物和活性氧簇的过量蓄积。大量研究表明,铁死亡不仅在重大慢性疾病的发生发展过程中发挥重要作用,而且在不同的疾病背景下扮演不同角色。目前认为,铁死亡可抑制肿瘤生长并增加多种肿瘤对化疗药物和免疫治疗的敏感性,因此诱导铁死亡的发生拓展了肿瘤治疗思路。然而,在心脑血管疾病和神经退行性疾病中,铁死亡的发生通过引发正常组织器官损伤和功能丧失直接参与疾病的发生、发展及转归,因此针对心脑血管疾病和神经退行性疾病,抑制铁死亡的发生能够有效预防并延缓这些疾病的发生和发展。本文综述了铁死亡在恶性肿瘤、神经退行性疾病和心脑血管疾病三类不同重大慢性疾病中的最新研究进展及其潜在的作用机制,系统讨论了靶向铁死亡在防治重大慢性疾病中的临床应用前景,为重大慢性疾病的防治提供新的依据。


关键词: 铁代谢障碍,  铁死亡,  肿瘤,  神经退行性疾病,  血管疾病,  综述 
Fig 1 Molecular mechanisms of ferroptosis
肿瘤类型 相关研究 参考文献
SLC7A11:溶质载体家族7成员11;Rb:成视网膜细胞瘤;MT1:金属硫蛋白1.
肝细胞癌 索拉非尼能够诱导肝细胞癌细胞发生铁死亡 [21]
成视网膜细胞瘤蛋白缺失肝细胞癌细胞对索拉非尼诱导的铁死亡更敏感 [22]
p62-Keap1-NRF2激活导致肝细胞癌细胞对铁死亡耐受 [23-26]
SLC7A11RbMT1表达水平与肝细胞癌患者预后相关 [22, 27-28]
胰腺癌 青蒿琥酯能够诱导胰腺导管腺癌细胞发生铁死亡 [29-30]
荜苃酰胺能诱导胰腺导管腺癌细胞发生铁死亡 [31]
荜苃酰胺、Cotylenin A和柳氮磺胺吡啶联用通过铁死亡有效抑制胰腺癌 [31]
肾细胞癌 相比其他肿瘤细胞,肾透明细胞癌细胞对谷胱甘肽过氧化物酶4抑制诱导的铁死亡更加敏感 [32]
HIF-2α-HILPDA通路调控肾透明细胞癌细胞对铁死亡的敏感性 [33]
TAZ-EMP1-NOX4通路调控肾透明细胞癌细胞对铁死亡的敏感性 [34-35]
乳腺癌 西拉美新和阿帕替尼联用上调铁水平并诱导乳腺癌细胞发生铁死亡 [36]
黏蛋白1C亚基、SLC7A11和CD44v形成复合物上调还原型谷胱甘肽表达,使三阴性乳腺癌细胞对铁死亡耐受 [37]
柳氮磺胺吡啶能抑制谷氨酰胺营养缺陷型三阴性乳腺癌细胞生长 [38]
SLC7A11与三阴性乳腺癌细胞的耐药和转移有密切联系 [39]
转铁蛋白受体表达水平与乳腺癌预后相关 [40-41]
Tab 1 Research progress on the role of ferroptosis in cancer
神经退行性疾病类型 相关研究 参考文献
Gpx4 :谷胱甘肽过氧化物酶4;GSTM2:谷胱甘肽S-转移酶Mu2.
阿尔茨海默病 脑脊液中铁蛋白水平能预测阿尔茨海默病发展进程 [56]
Gpx4诱导性敲除小鼠海马神经元死亡和认知能力下降 [57]
过表达或增加磷酸化τ蛋白能诱导神经元铁死亡,α硫辛酸可抑制τ蛋白诱导的铁死亡 [58]
帕金森病 蛋白激酶C激活可引发铁死亡 [59]
丝氨酸/苏氨酸蛋白激酶参与Erastin诱导的铁死亡 [60]
星形胶质细胞为神经元提供GSTM2,保护神经元免受氧化损伤 [61-63]
肌萎缩侧索硬化 神经元Gpx4诱导性敲除小鼠出现肌萎缩侧索硬化症状 [57]
Tab 2 Research progress on the role of ferroptosis in neurodegenerative diseases
心脑血管疾病类型 相关研究 参考文献
缺血再灌注 离体小鼠心脏缺血再灌注模型中,抑制谷氨酰胺代谢可减轻铁死亡引发的心脏损伤 [95]
铁死亡抑制剂和铁螯合剂可有效缓解小鼠心脏缺血再灌注引发的心肌损伤 [96]
阿霉素诱导心肌损伤 阿霉素通过血红素加氧酶诱导心肌细胞发生铁死亡;铁蓄积和脂质过氧化主要发生于线粒体 [96]
血红素加氧酶抑制剂、铁死亡抑制剂、线粒体抗氧化抑制剂、铁螯合剂等可有效逆转阿霉素引发的心肌损伤 [96]
心脏移植后心肌损伤 铁死亡调控小鼠心脏移植后中性粒细胞的募集 [97]
缺血性脑卒中 缺氧诱导因子脯氨酰羟化酶可能是铁螯合剂抑制神经元铁死亡的潜在靶点 [98]
抑制铁死亡能够保护大脑中动脉阻塞小鼠神经元,铁与τ蛋白的相互作用存在多效调控 [99]
出血性脑卒中 (-)-表儿茶素通过减少大脑铁蓄积和铁死亡相关蛋白表达缓解出血性脑卒中早期脑损伤 [100]
铁死亡抑制剂可减轻脑切片中神经元死亡及出血性脑卒中小鼠模型中神经元死亡 [101-102]
增加谷胱甘肽过氧化物酶4表达能避免神经元发生铁死亡而改善预后 [103]
Tab 3 Research progress on the role of ferroptosis in cardiovascular and cerebrovascular diseases
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