Nuclear receptor coactivator 4-mediated ferritinophagy contributes to cerebral ischemia-induced ferroptosis in ischemic stroke
Nuclear receptor coactivator 4-mediated ferritinophagy contributes to cerebral ischemia-induced ferroptosis in ischemic stroke
复制标题
核受体共激活剂4介导的铁蛋白自噬导致缺血性中风中脑缺血诱导的铁死亡
DOI：
10.1016/j.phrs.2021.105933
复制
发表时间：
2021-10-23
影响因子：
9.3
通讯作者：
Ji, Jing
中科院分区：
文献类型：
--
作者：
Li, Chong;Sun, Guangchi;Ji, Jing
缺血性中风由于其高致残率和死亡率而构成显著的健康风险。为了解决这个问题，已经提出了几种治疗方法，包括靶向程序性细胞死亡（PCD）的中断。铁凋亡是一种新定义的PCD，其特征是铁依赖性脂质过氧化积累，并正在成为治疗许多疾病的有希望的靶点。为探讨缺血性脑卒中中铁凋亡的发生和执行机制，我们建立了脑卒中模型，并在体内外模拟缺血/再灌注（I/R）神经元损伤。与以往关于中风的报道不同，我们通过测量核心蛋白（如ACSL 4、15-LOX 2、铁蛋白和GPX 4）的水平来检测铁凋亡。此外，I/R损伤通过自噬途径诱导铁蛋白的过度降解和随后神经元中游离铁的增加。这种现象最近被称为铁蛋白吞噬，并报道在一些细胞系中受核受体辅激活因子4（NCOA 4）的调节。我们的研究中检测到细胞质中增加的NCOA 4，然后用shRNA沉默以研究其功能。在体内和体外，NCOA 4的缺失显着废除由I/R损伤引起的铁蛋白吞噬，从而抑制铁凋亡。此外，我们发现，NCOA 4是上调泛素特异性肽酶14（USP 14）通过去泛素化过程中受损的神经元，我们发现的证据表明，药理学抑制USP 14有效地降低NCOA 4水平，以保护神经元从铁蛋白吞噬介导的铁凋亡。这些发现为治疗缺血性卒中提供了一个新的有效靶点。
Ischemic stroke poses a significant health risk due to its high rate of disability and mortality. To address this problem, several therapeutic approaches have been proposed, including interruption targeting programmed cell death (PCD). Ferroptosis is a newly defined PCD characterized by iron-dependent accumulation of lipid peroxidation, and is becoming a promising target for treating numerous diseases. To explore the underlying mechanisms of the initiation and execution of ferroptosis in ischemic stroke, we established stroke models in vivo and in vitro simulating ischemia/reperfusion (I/R) neuronal injury. Different from previous reports on stroke, we tested ferroptosis by measuring the levels of core proteins, such as ACSL4, 15-LOX2, Ferritin and GPX4. In addition, I/R injury induces excessive degradation of ferritin via the autophagy pathway and subsequent increase of free iron in neurons. This phenomenon has recently been termed ferritinophagy and reported to be regulated by nuclear receptor coactivator 4 (NCOA4) in some cell lines. Increased NCOA4 in cytoplasm was detected in our study and then silenced by shRNA to investigate its function. Both in vivo and in vitro, NCOA4 deletion notably abrogated ferritinophagy caused by I/R injury and thus inhibited ferroptosis. Furthermore, we found that NCOA4 was upregulated by ubiquitin specific peptidase 14 (USP14) via a deubiquitination process in damaged neurons, and we found evidence of pharmacological inhibition of USP14 effectively reducing NCOA4 levels to protect neurons from ferritinophagy-mediated ferroptosis. These findings suggest a novel and effective target for treating ischemic stroke.