Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice PY2014 IR95 教材

 Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice PY2014 IR95 教材

https://pubmed.ncbi.nlm.nih.gov/25402683/

Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice PY2014 IR95 教材

0001 Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. (使鐵死亡調節因子 Gpx4 失去活性會在小鼠引發急性腎衰竭。)

0002 Abstract (摘要)

0003 Ferroptosis is a non-apoptotic form of cell death induced by small molecules in specific tumour types, and in engineered cells overexpressing oncogenic RAS. (鐵死亡是一種非細胞凋亡形式的細胞死亡，可由小分子化合物在特定類型的腫瘤細胞，以及過度表現致癌性 RAS 的工程化細胞中誘導。)

0004 Yet, its relevance in non-transformed cells and tissues is unexplored and remains enigmatic. (然而，鐵死亡與非轉化細胞及組織之間的相關性尚未被探索，至今仍是一個難解的謎。)

0005 Here, we provide direct genetic evidence that the knockout of glutathione peroxidase 4 (Gpx4) causes cell death in a pathologically relevant form of ferroptosis. (在本研究中，我們提供了直接的遺傳學證據，證明麩胱甘肽過氧化物酶 4（Gpx4）的基因剔除，會以一種具有病理學意義的鐵死亡形式導致細胞死亡。)

0006 Using inducible Gpx4(-/-) mice, we elucidate an essential role for the glutathione/Gpx4 axis in preventing lipid-oxidation-induced acute renal failure and associated death. (利用可誘導型 Gpx4(-/-) 小鼠，我們闡明了穀胱甘肽／Gpx4 軸在防止脂質氧化所誘發的急性腎衰竭及其相關死亡方面所扮演的關鍵作用。)

0007 We furthermore systematically evaluated a library of small molecules for possible ferroptosis inhibitors, leading to the discovery of a potent spiroquinoxalinamine derivative called Liproxstatin-1, which is able to suppress ferroptosis in cells, in Gpx4(-/-) mice, and in a pre-clinical model of ischaemia/reperfusion-induced hepatic damage. (此外，我們系統性地評估了一系列小分子化合物，以尋找可能的鐵死亡抑制劑，並因此發現了一種名為 Liproxstatin-1 的強效螺環喹喔啉胺衍生物；它能夠抑制細胞中的鐵死亡，也能在 Gpx4(-/-) 小鼠以及缺血／再灌流所誘發的肝損傷臨床前模型中抑制鐵死亡。)

0008 In sum, we demonstrate that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection. (總而言之，我們證明鐵死亡是一種廣泛存在且具有動態性的細胞死亡形式；當鐵死亡受到阻止時，有望產生顯著的細胞保護作用。)

0009 PubMed Disclaimer (PubMed 免責聲明)

0010 Conflict of interest statement (利益衝突聲明)

0011 COMPETING FINANCIAL INTERESTS (競爭性財務利益)

0012 The authors declare that a patent application has been filed for some of the compounds described in this work. (作者聲明，針對本研究所描述的部分化合物，已經提出專利申請。)

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Abstract

Ferroptosis is a non-apoptotic form of cell death induced by small molecules in specific tumour types, and in engineered cells overexpressing oncogenic RAS. Yet, its relevance in non-transformed cells and tissues is unexplored and remains enigmatic. Here, we provide direct genetic evidence that the knockout of glutathione peroxidase 4 (Gpx4) causes cell death in a pathologically relevant form of ferroptosis. Using inducible Gpx4(-/-) mice, we elucidate an essential role for the glutathione/Gpx4 axis in preventing lipid-oxidation-induced acute renal failure and associated death. We furthermore systematically evaluated a library of small molecules for possible ferroptosis inhibitors, leading to the discovery of a potent spiroquinoxalinamine derivative called Liproxstatin-1, which is able to suppress ferroptosis in cells, in Gpx4(-/-) mice, and in a pre-clinical model of ischaemia/reperfusion-induced hepatic damage. In sum, we demonstrate that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection.

PubMed Disclaimer

Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare that a patent application has been filed for some of the compounds described in this work.

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