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铁死亡调控蛋白gpx4的小分子抑制剂研究进展

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药学实践与服务 2024年第9期42卷 375-378页

作者：刘汝雄杨万镇涂杰盛春泉海军军医大学药学系药物化学教研室上海200433

铁死亡(ferroptosis)是2012年新发现的一种非凋亡坏死的细胞死亡方式,其主要特征为脂质活性氧增多以及细胞内亚铁离子累积。谷胱甘肽过氧化物酶4(gpx4)是含硒gpx家族第4位成员,是细胞清除脂质过氧化物的重要蛋白,也是铁死亡的重要调节... 详细信息

铁死亡(ferroptosis)是2012年新发现的一种非凋亡坏死的细胞死亡方式,其主要特征为脂质活性氧增多以及细胞内亚铁离子累积。谷胱甘肽过氧化物酶4(gpx4)是含硒gpx家族第4位成员,是细胞清除脂质过氧化物的重要蛋白,也是铁死亡的重要调节因子。靶向gpx4小分子抑制剂能诱导铁死亡发生,为治疗耐药性癌症和神经退行性疾病提供了新的策略。主要介绍gpx4蛋白的结构和功能,并综述gpx4小分子抑制剂最新前沿进展,为开发基于GXP4抑制的铁死亡诱导剂提供研究基础。

关键词： gpx4 小分子抑制剂铁死亡谷胱甘肽脂质过氧化

硒和蛋白质与大鼠心肌gpx1、gpx4表达及翻译

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中国地方病防治 2011年第1期26卷 4-6页

作者：刘春旭李少臣陈洁刘明法闫丽佳王艺如张辉裴俊瑞周令望侯杰张立君王铜哈尔滨医科大学中国疾病预防控制中心地方病控制中心克山病研究所黑龙江150081 浙江省嘉兴市秀洲区卫生监督所北京市朝阳区高碑店社区卫生服务中心保健科天津市塘沽区疾病预防控制中心北京市昌平区小汤山社区卫生服务中心

目的研究硒和蛋白质对大鼠心肌gpx1、gpx4表达及其翻译过程的影响。方法 60只雄性Wistar大鼠按硒与蛋白质两因素两水平的析因设计随机分为四组,饲养一年后处死,western blot方法检测心肌gpx1、gpx4和SBP2蛋白表达水平;RT-PCR方法扩增心... 详细信息

目的研究硒和蛋白质对大鼠心肌gpx1、gpx4表达及其翻译过程的影响。方法 60只雄性Wistar大鼠按硒与蛋白质两因素两水平的析因设计随机分为四组,饲养一年后处死,western blot方法检测心肌gpx1、gpx4和SBP2蛋白表达水平;RT-PCR方法扩增心肌gpx1、gpx4 mRNA上SECIS序列,SSCP法确定其基因型后进行碱基序列测定。结果低硒组心肌组织gpx1、gpx4含量低于常硒组(Pgpx1含量低于常蛋白组(Pgpx1表达方面有交互作用(Pgpx1、gpx4基因的SECIS碱基序列并未发生变异。结论在低硒低蛋白条件下,心肌gpx1和gpx4含量显著降低,而SBP2含量则增加;gpx1、gpx4基因的SECIS碱基序列并未发生变异。

关键词：硒 gpx1 gpx4 SBP2 SECIS

枸杞多糖通过SLC7A11/gpx4通路抑制铁死亡减轻小鼠脑缺血再灌注损伤

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神经解剖学杂志 2024年第05期40卷 607-612页

作者：邱政皓马雅萍马昌盛韩博孟姝辰白敏贺茂涛山东第二医科大学基础医学院山东第二医科大学附属医院

目的:探讨枸杞多糖（LBP）是否通过溶质载体家族7成员11（SLC7A11）/谷胱甘肽过氧化酶4（gpx4）通路抑制铁死亡进而减轻脑缺血再灌注损伤。方法:使用大脑中动脉栓塞（MCAO）方法建立小鼠脑缺血再灌注（I/R）损伤模型，并同时给予枸杞多... 详细信息

目的:探讨枸杞多糖（LBP）是否通过溶质载体家族7成员11（SLC7A11）/谷胱甘肽过氧化酶4（gpx4）通路抑制铁死亡进而减轻脑缺血再灌注损伤。方法:使用大脑中动脉栓塞（MCAO）方法建立小鼠脑缺血再灌注（I/R）损伤模型，并同时给予枸杞多糖处理。小鼠被随机分为3组：假手术（Sham）组，I/R组，以及I/R+LBP组。使用2,3,5氯化三苯基四氮唑（TTC）染色来观察脑梗死体积；通过神经功能缺损评分来评估小鼠的神经功能；利用超氧化物歧化酶（SOD）、谷胱甘肽（GSH）、丙二醛（MDA）和亚铁离子(Fe2+)检测试剂盒来检测SOD、GSH、MDA和Fe2+的水平变化；利用Western Blot检测抗铁死亡相关蛋白，包括SLC7A11、gpx4以及核因子红细胞系2相关因子2（Nrf2）的表达情况。结果:枸杞多糖能够减少I/R小鼠的脑梗死体积，改善I/R小鼠神经功能；枸杞多糖增加I/R损伤小鼠中SOD和GSH的含量、减少MDA的含量；Western Blot结果：I/R组脑组织中抗铁死亡相关蛋白SLC7A11、gpx4、Nrf2的表达水平明显低于Sham组；而通过枸杞多糖处理后，I/R+LBP组中SLC7A11、gpx4、Nrf2的水平明显高于I/R组。结论:枸杞多糖可能通过SLC7A11/gpx4信号通路抑制铁死亡来减轻脑缺血再灌注损伤。枸杞多糖对脑缺血再灌注损伤具有神经保护作用，是一种潜在的神经保护剂。

关键词：枸杞多糖缺血再灌注损伤 SLC7A11 gpx4 铁死亡小鼠

缺血性脑卒中铁死亡特征基因NFE2L2的鉴定与验证

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中国组织工程研究 2025年第7期29卷 1466-1474页

作者：王咪马书杰刘杨齐瑞上海中医药大学附属岳阳中西医结合医院康复医学科上海市200437 上海中医药大学上海市201203 上海市第二康复医院上海市200431

背景:铁死亡与缺血性脑卒中的发病密切相关,靶向铁死亡是一种治疗缺血性脑卒中有前景的方案,但具体调控靶点尚不明确。目的:通过生物信息学和机器学习方法筛选缺血性脑卒中铁死亡相关特征基因,并通过细胞实验进行验证,探讨铁死亡在缺血... 详细信息

背景:铁死亡与缺血性脑卒中的发病密切相关,靶向铁死亡是一种治疗缺血性脑卒中有前景的方案,但具体调控靶点尚不明确。目的:通过生物信息学和机器学习方法筛选缺血性脑卒中铁死亡相关特征基因,并通过细胞实验进行验证,探讨铁死亡在缺血性脑卒中的作用。方法:基于GEO数据库和FerrDb数据库选取符合条件的缺血性脑卒中相关数据集和铁死亡表达数据集,通过t检验筛选铁死亡相关差异基因。对铁死亡相关差异基因进行GO功能富集分析与KEGG信号通路富集分析。通过PPI网络分析和机器学习筛选缺血性脑卒中铁死亡的特征基因,利用ROC分析和GSEA分析探究特征基因的准确性和生物功能。然后进行细胞实验,将HT22细胞分为对照组与缺血性脑卒中组,对照组不作任何干预,缺血性脑卒中组加入0.1 mol/L的H_(2)O_(2)干预24 h诱导细胞氧化应激和铁死亡,通过实时荧光定量RT-PCR和Western Blot验证铁死亡的发生和特征基因表达。结果与结论:(1)共获取45个铁死亡相关差异基因,GO和KEGG富集分析发现差异基因与氧化应激、自噬、铁死亡、脂肪细胞因子信号通路和线粒体代谢密切相关。(2)通过PPI网络中的MCODE插件和cytoHubba插件与机器学习中的LASSO算法和SVM-RFE算法共鉴定出1个铁死亡特征基因核因子E2相关因子2(nuclear factor erythroid 2-related factor 2,NFE2L2)。(3)对NFE2L2进行ROC曲线分析,发现在训练集和验证集中构建的诊断预测模型具有良好的准确性与特异性;对NFE2L2进行GSEA分析,发现特征基因通过免疫、炎症反应、氨基酸代谢及神经因子调控等方面参与缺血性脑卒中发病机制的调控。(4)细胞实验的RT-PCR和Western Blot分析表明,与对照组对比,缺血性脑卒中组中的酰基辅酶A合成酶长链家族成员4 mRNA和蛋白表达水平显著增高(P4 mRNA和蛋白表达水平显著降低(P<0.05);与对照组对比,缺血性脑卒中组中特征基因NFE2L2 mRNA和蛋白表达水平显著增高(P<0.05)。(5)上述结果证实,缺血性脑卒中与铁死亡密切相关,靶向特征基因NFE2L2可以为研究和治疗缺血性脑卒中提供一定的思路与方向。

关键词：缺血性脑卒中铁死亡生物信息学 HT22细胞机器学习特征基因细胞实验 NFE2L2 ASCL4 gpx4

Ferroptosis,radiotherapy,and combination therapeutic strategies

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Protein & Cell 2021年第11期12卷 836-857页

作者： Guang Lei Chao Mao Yuelong Yan Li Zhuang Boyi Gan Department of Radiation Oncology Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangsha 410013China Department of Experimental Radiation Oncology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences HoustonTXUSA

Ferroptosis,an iron-dependent form of regulated cell death driven by peroxidative damages of polyunsatu-rated-fatty-acid-containing phospholipids in cellular membranes,has recently been revealed to play an important role in radiotherapy-induced cell death and tumor suppression,and to mediate the synergy between radiotherapy and *** this review,we summarize known as well as putative mechanisms underlying the crosstalk between radiotherapy and fer-roptosis,discuss the interactions between ferroptosis and other forms of regulated cell death induced by radiotherapy,and explore combination therapeutic strategies targeting ferroptosis in radiotherapy and *** review will provide important frameworks for future investigations of ferroptosis in cancer therapy.

关键词： ferroptosis lipid peroxidation gpx4 SLC7A11 radiotherapy immunotherapy radiosensitization combination therapy

Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis

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Neural Regeneration Research 2019年第3期14卷 532-541页

作者： Xue Yao Yan Zhang Jian Hao Hui-Quan Duan Chen-Xi Zhao Chao Sun Bo Li Bao-You Fan Xu Wang Wen-Xiang Li Xuan-Hao Fu Yong Hu Chang Liu Xiao-Hong Kong Shi-Qing Feng Department of Orthopedics Tianjin Medical University General Hospital State Key Laboratory of Medicinal Chemical Biology Nankai University International Science and Technology Cooperation Base of Spinal Cord Injury Department of Orthopedics Nankai Hospital Department of Orthopedic and Traumatology The University of Hong Kong Pokfulam Hong Kong Special Administrative Region School of Medicine Nankai University Tianjin Neurological Institute Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System Ministry of Education and Tianjin City

Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition represents the mechanism of action of Deferoxamine on spinal cord injury recovery. A rat model of Deferoxamine at thoracic 10 segment was established using a modified Allen's method. Ninety 8-week-old female Wistar rats were used. Rats in the Deferoxamine group were intraperitoneally injected with 100 mg/kg Deferoxamine 30 minutes before injury. Simultaneously, the Sham and Deferoxamine groups served as controls. Drug administration was conducted for 7 consecutive days. The results were as follows:(1) Electron microscopy revealed shrunken mitochondria in the spinal cord injury group.(2) The Basso, Beattie and Bresnahan locomotor rating score showed that recovery of the hindlimb was remarkably better in the Deferoxamine group than in the spinal cord injury group.(3) The iron concentration was lower in the Deferoxamine group than in the spinal cord injury group after injury.(4) Western blot assay revealed that, compared with the spinal cord injury group, gpx4, xCT, and glutathione expression was markedly increased in the Deferoxamine group.(5) Real-time polymerase chain reaction revealed that, compared with the Deferoxamine group, mRNA levels of ferroptosis-related genes Acyl-CoA synthetase family member 2(ACSF2) and iron-responsive element-binding protein 2(IREB2) were up-regulated in the Deferoxamine group.(6) Deferoxamine increased survival of neurons and inhibited gliosis. These findings confirm that Deferoxamine can repair spinal cord injury by inhibiting ferroptosis. Targeting ferroptosis is therefore a promising therapeutic approach for spinal cord injury.

关键词： nerve regeneration iron spinal cord injury secondary injury ferroptosis deferoxamine gpx4 xCT treatment astrogliosis lipid peroxidation neural regeneration

Identification of ferroptosis as a novel mechanism for antitumor activity of natural product derivative a2 in gastric cancer

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Acta Pharmaceutica Sinica B 2021年第6期11卷 1513-1525页

作者： Ying Liu Zan Song Yajie Liu Xubin Ma Wang Wang Yu Ke Yichao Xu Dequan Yu Hongmin Liu State Key Laboratory of Esophageal Cancer Prevention&Treatment Key Laboratory of Advanced Drug Preparation TechnologiesHenan Key Laboratory of Drug Quality Control&EvaluationSchool of Pharmaceutical SciencesZhengzhou UniversityMinistry of Education of ChinaZhengzhou 450001China State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation,thus stimulating ferroptosis may be a potential strategy for treating gastric cancer,therapeutic agents against which are urgently *** oridonin A(JDA) is a natural compound isolated from Jiyuan Rabdosia rubescens with anti-tumor activity,unclear anti-tumor mechanisms and limited water solubility hamper its clinical ***,we showed a2,a new JDA derivative,inhibited the growth of gastric cancer ***,we discovered for the first time that a2 induced ***,compound a2 decreased gpx4 expression and overexpressing gpx4 antagonized the anti-proliferative activity of ***,we demonstrated that a2 caused ferrous iron accumulation through the autophagy pathway,prevention of which rescued a2 induced ferrous iron elevation and cell growth ***,a2 exhibited more potent anti-cancer activity than 5-fluorouracil in gastric canc er cell line-derived xenograft mice ***-derived tumor xenograft models from different patients displayed varied sensitivity to a2,and gpx4 downregulation indicated the sensitivity of tumors to ***,a2 exhibited well pharmacokinetic characteristic ***,our data suggest that inducing ferroptosis is the major mechanism mediating anti-tumor activity of a2,and a2 will hopefully serve as a promising compound for gastric cancer treatment.

关键词： Jiyuan Rabdosia rubescens JDA derivative Gastric cancer Ferroptosis ROS gpx4 Ferrous iron Autophagy

Erythropoietin inhibits ferroptosis and ameliorates neurological function after spinal cord injury

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Neural Regeneration Research 2023年第4期18卷 881-888页

作者： Yu Kang Rui Zhu Shuang Li Kun-Peng Qin Hao Tang Wen-Shan Shan Zong-Sheng Yin Department of Orthopedics The First Affiliated Hospital of Anhui Medical UniversityHefeiAnhui ProvinceChina

Ferroptosis is one of the critical pathological events in spinal cord *** has been reported to improve the recovery of spinal cord ***,whether ferroptosis is involved in the neuroprotective effects of erythropoietin on spinal cord injury has not been *** this study,we established rat models of spinal cord injury by modified Allen’s method and intraperitoneally administered 1000 and 5000 IU/kg erythropoietin once a week for 2 successive *** low and high doses of erythropoietin promoted recovery of hindlimb function,and the high dose of erythropoietin led to better *** dose of erythropoietin exhibited a stronger suppressive effect on ferroptosis relative to the low dose of *** effects of erythropoietin on inhibiting ferroptosis-related protein expression and restoring mitochondrial morphology were similar to those of Fer-1(a ferroptosis suppressor),and the effects of erythropoietin were largely diminished by RSL3(ferroptosis activator).In vitro experiments showed that erythropoietin inhibited RSL3-induced ferroptosis in PC12 cells and increased the expression of xCT and *** suggests that xCT and gpx4 are involved in the neuroprotective effects of erythropoietin on spinal cord *** findings reveal the underlying anti-ferroptosis role of erythropoietin and provide a potential therapeutic strategy for treating spinal cord injury.

关键词： erythropoietin ferroptosis gpx4 iron overload lipid peroxidation mechanism neurological function recovery spinal cord injury spinal neuron xCT

Neuroprotective effects of neural stem cells pretreated with neuregulin1β on PC12 cells exposed to oxygen-glucose deprivation/reoxygenation

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Neural Regeneration Research 2023年第3期18卷 618-625页

作者： Qiu-Yue Zhai Yuan-Hua Ye Yu-Qian Ren Zhen-Hua Song Ke-Li Ge Bao-He Cheng Yun-Liang Guo Institute of Cerebrovascular Diseases Medical Research CenterThe Affiliated Hospital of Qingdao UniversityTaishan Scholars Construction Project Excellent Innovative Team of Shandong ProvinceQingdaoShandong ProvinceChina Department of Obstetrics The Affiliated Hospital of Qingdao UniversityQingdaoShandong ProvinceChina Research Center of Stem Cells Shandong Haoyun International Hospital of Stem CellsJinanShandong ProvinceChina

Studies on ischemia/reperfusion(I/R)injury suggest that exogenous neural stem cells(NSCs)are ideal candidates for stem cell therapy reperfusion ***,NSCs are difficult to obtain owing to ethical *** addition,the survival,differentiation,and proliferation rates of transplanted exogenous NSCs are low,which limit their clinical *** previous study showed that neuregulin1β(NRG1β)alleviated cerebral I/R injury in *** this study,we aimed to induce human umbilical cord mesenchymal stem cells into NSCs and investigate the improvement effect and mechanism of NSCs pretreated with 10 nM NRG1βon PC12 cells injured by oxygen-glucose deprivation/reoxygenation(OGD/R).Our results found that 5 and 10 nM NRG1βpromoted the generation and proliferation of ***-culture of NSCs and PC12 cells under condition of OGD/R showed that pretreatment of NSCs with NRG1βimproved the level of reactive oxygen species,malondialdehyde,glutathione,superoxide dismutase,nicotinamide adenine dinucleotide phosphate,and nuclear factor erythroid 2-related factor 2(Nrf2)and mitochondrial damage in injured PC12 cells;these indexes are related to *** has reported that p53 and solute carrier family 7 member 11(SLC7A11)play vital roles in ferroptosis caused by cerebral I/R *** data show that the expression of p53 was increased and the level of glutathione peroxidase 4(gpx4)was decreased after RNA interference-mediated knockdown of SLC7A11 in PC12 cells,but this change was alleviated after co-culturing NSCs with damaged PC12 *** findings suggest that NSCs pretreated with NRG1βexhibited neuroprotective effects on PC12 cells subjected to OGD/R through influencing the level of ferroptosis regulated by p53/SLC7A11/gpx4 pathway.

关键词： ferroptosis p53 SLC7A11 gpx4 human umbilical cord-mesenchymal stem cells neural stem cells neuregulin1β neuroprotection oxygen-glucose deprivation/reoxygenation PC12 cell