Control of Ferroptosis and Acute Tubular Necrosis by Female Sex Hormones and Estrogen Derivatives

60多年来，人们已经认识到女性组织对缺血再灌注损伤(IRI)具有抵抗力，但其潜在机制仍不清楚。在过去的十年中，研究已经提供了越来越多的证据表明铁下垂有助于不同器官的IRI。在这里，我们发现分离的肾小管对铁性下垂有部分抵抗力，我们的初步数据进一步表明，在铁性下垂过程中，细胞死亡传播可能被雌性激素，如17β-雌二醇及其代谢产物所抑制。这些观察结果使我们得出了一个中心假设，即雌二醇衍生物通常起着铁下垂抑制剂的作用。在这里，我们建议系统和详细地研究：1)女性性激素的抗铁链活性；2)肾小管脂质和脂类的相关变化；3)氧化还原酶如铁下垂抑制蛋白1(FSP1)在无细胞系统和体内对过氧化雌二醇的再生。这一独特的实验装置将使我们能够得出结论，在急性肾小管坏死和急性肾损伤中，雌激素介导的铁性下垂的控制机制。

It has been recognized for longer than 6 decades that female tissues are resistant to ischemia-reperfusion injury (IRI), but an underlying mechanism remains elusive. Research during the last ten years has provided accumulating evidence for ferroptosis to contribute to IRI of various organs. Here, we identify isolated kidney tubules to be partially resistant to ferroptosis, and our preliminary data further indicate cell death propagation during ferroptosis of isolated kidney tubules to be inhibited by female sex hormones, such as 17beta-estradiol and its metabolites. These observations led us to the central hypothesis that estradiol derivatives function as ferroptosis inhibitors in general. Here, we propose to investigate systematically and in detail i) the antiferroptotic potency of female sex hormones, ii) the associated changes in lipid and oxilipid profiles of kidney tubules and iii) the regeneration of peroxidzed estradiols by oxidoreductases such as ferroptosis suppressor protein 1 (FSP1) in cell free systems and in vivo. This unique experimental setup will allow us to conclude on the mechanisms of estradiol-mediated control of ferroptosis in acute tubular necrosis and acute kidney injury.