Defining the functions and translational potential of ferroptosis

定义铁死亡的功能和转化潜力

• 批准号: 10478855
• 负责人: Brent R Stockwell
• 金额: $ 92.65万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-02 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478855
• 关键词: Automobile Driving; Cell Death; Goals; Lipid Peroxidation; Lipids; Malignant Neoplasms; Nutrient; Oxidative Stress; Pathway interactions; Process; Research; Signal Transduction; Tumor Suppression; experience; glutathione peroxidase; oxidative damage; repair enzyme; repaired; small molecule; translational potential; tumor

Ferroptosis in a new form of regulated, non-apoptotic cell death that we discovered; we have determined the major mechanisms regulating activation of ferroptosis and several contexts where it can be induced in sensitized tumors. We found that ferroptosis is ultimately characterized by excessive lipid peroxidation upon loss of activity of the lipid repair enzyme glutathione peroxidase 4 (Gpx4). We propose here the hypothesis that lipid peroxidation serves as a signal to detect a scarcity of nutrients needed tor repair of oxidative damage, and that ferroptosis serves as an innate tumor suppression mechanism to eliminate nascent tumors experiencing such oxidative stress. We further propose to elucidate mechanisms driving ferroptosis in specific cancer contexts, and whether it is feasible to create precision small molecule activators of ferroptosis that eliminate tumors that have become addicted to this repair pathway.

我们发现的新型非凋亡细胞死亡的新形式的铁凋亡；我们 已经确定了调节铁凋亡激活的主要机制和几种 可以在敏化肿瘤中诱导的上下文。我们发现铁铁作用是 最终以脂质活性流失后过度脂质过氧化为特征 修复酶谷胱甘肽过氧化物酶4（GPX4）。我们在这里提出了这样一个假设 脂质过氧化可作为检测需要修复营养的稀缺性的信号 氧化损伤，而铁铁作用可作为先天性肿瘤 消除具有这种氧化应激的新生肿瘤的机制。我们进一步 提议阐明在特定癌症环境中驱动铁凋亡的机制，并 是否可以创建精确的小分子激活螺栓杀伤剂，这是可行的 消除已上瘾的修复途径的肿瘤。

项目成果

A Mitochondrial-Targeted Nitroxide Is a Potent Inhibitor of Ferroptosis.

• DOI: 10.1021/acscentsci.6b00199
• 发表时间: 2016-09-28
• 期刊: ACS CENTRAL SCIENCE
• 影响因子: 18.2
• 作者: Krainz, Tanja;Gaschler, Michael M.;Lim, Chaemin;Sacher, Joshua R.;Stockwell, Brent R.;Wipf, Peter
• 通讯作者: Wipf, Peter

Vitamin K: A new guardian against ferroptosis.

维生素 K：预防铁死亡的新卫士。

• DOI: 10.1016/j.molcel.2022.10.001
• 发表时间: 2022
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Hirschhorn,Tal;Stockwell,BrentR
• 通讯作者: Stockwell,BrentR

Elucidating Compound Mechanism of Action by Network Perturbation Analysis.

• DOI: 10.1016/j.cell.2015.05.056
• 发表时间: 2015-07-16
• 期刊: Cell
• 影响因子: 64.5
• 作者: Woo JH;Shimoni Y;Yang WS;Subramaniam P;Iyer A;Nicoletti P;Rodríguez Martínez M;López G;Mattioli M;Realubit R;Karan C;Stockwell BR;Bansal M;Califano A
• 通讯作者: Califano A

Ferroptosis: Death by Lipid Peroxidation.

• DOI: 10.1016/j.tcb.2015.10.014
• 发表时间: 2016-03
• 期刊: Trends in cell biology
• 影响因子: 19
• 作者: Yang WS;Stockwell BR
• 通讯作者: Stockwell BR

Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility.

• DOI: 10.1016/j.bmcl.2015.07.018
• 发表时间: 2015-11-01
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Larraufie MH;Yang WS;Jiang E;Thomas AG;Slusher BS;Stockwell BR
• 通讯作者: Stockwell BR