Steroid Hormones as Regulators of Ferroptosis Sensitivity During Acute Kidney Injury

地塞米松和其他类固醇激素是广泛使用的药物，其使用超出了自身免疫性疾病或预防移植排斥的最常见应用。已知副作用限制了类固醇的适用剂量，但尽管广泛的临床使用，尚未描述任何决定性的作用机制来解释不良功能。作为我们以前关于肾上腺皮质癌对铁凋亡的敏感性的工作的延续，我们提供了类固醇激素在已建立的细胞培养试验中显着降低铁凋亡阈值的初步数据。此外，我们最近发现两种啮齿动物品系，铁凋亡抑制蛋白1（FSP1）缺陷型和谷胱甘肽过氧化物酶4（GPX4）突变型小鼠，在急性肾损伤（阿基）小鼠模型中对铁凋亡诱导表现出非凡的敏感性。在这里，我们建议联合收割机这两个结果进行一组工作包，允许测试类固醇激素介导的促进铁凋亡的中心假设。我们的目的是更详细地描述类固醇激素在细胞系中促进铁凋亡的作用，并评估类固醇激素在原发性肾组织中对铁凋亡的调节。最后，我们将阐明类固醇激素对小鼠阿基的作用，并阐明FSP1或GPX4是否直接受类固醇调节，或者是否涉及尚未确定的监测系统。该项目符合SPP 3206的目标和框架。

Dexamethasone and other steroid hormones are widely used drugs, the use of which goes beyond the most common applications of autoimmune diseases or the prevention of transplant rejection. Side effects have been known to limit the applicable dosage of steroids, but despite the widespread clinical use, no conclusive mechanism of action has been described to explain the untoward functions. As a continuation of our previous work on the exquisite sensitivity of adrenocortical carcinomas to ferroptosis, we provide preliminary data for steroid hormones to significantly lower the threshold to ferroptosis in established cell culture assays. In addition, we recently found two rodent strains, ferroptosis suppressor protein 1 (FSP1)-deficient and glutathione peroxidase 4 (GPX4)-mutated mice, to exhibit extraordinary sensitivity to ferroptosis induction in mouse models of acute kidney injury (AKI). Here, we propose to combine these two findings to perform a set of work packages which allow testing the central hypothesis of steroid hormone-mediated promotion of ferroptosis. We aim to characterize the ferroptosis promoting effect of steroid hormones in cell lines in more detail and assess ferroptosis regulation by steroid hormones in primary renal tissue. We will finally elucidate the role of steroid hormones on AKI in mice and clarify if FSP1 or GPX4 are directly regulated by steroids, or, alternatively, if yet undefined surveillance systems are involved. This project aligns with the aims and framework of the SPP3206.