Sha Wenxin, Hu Fei, Xi Yang, Chu Yudong, Bu Shizhong
Diabetes Research Center, School of Medicine, Ningbo University, Ningbo 315211, China.
Cixi Biomedical Research Institute, Wenzhou Medical University, Cixi 315300, China.
J Diabetes Res. 2021 Jun 28;2021:9999612. doi: 10.1155/2021/9999612. eCollection 2021.
Ferroptosis is a novel form of nonapoptotic regulated cell death (RCD). It features iron-dependent lipid peroxide accumulation accompanied by inadequate redox enzymes, especially glutathione peroxidase 4 (GPX4). RAS-selective lethal 3 (RSL3), erastin, and ferroptosis inducing 56 (FIN56) induce ferroptosis via different manners targeting GPX4 function. Acyl-CoA synthetase long-chain family 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and lipoxygenases (LOXs) participate in the production of lipid peroxides. Heat shock protein family B member 1 (HSPB1) and nuclear receptor coactivator 4 (NCOA4) regulate iron homeostasis preventing ferroptosis caused by the high concentration of intracellular iron. Ferroptosis is ubiquitous in our body as it exists in both physiologic and pathogenic processes. It is involved in glucose-stimulated insulin secretion (GSIS) impairment and arsenic-induced pancreatic damage in the pathogenesis of diabetes. Moreover, iron and the iron-sulfur (Fe-S) cluster influence each other, causing mitochondrial iron accumulation, more reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, failure in biosynthesis of insulin, and ferroptosis in -cells. In addition, ferroptosis also engages in the pathogenesis of diabetic complications such as myocardial ischemia and diabetic cardiomyopathy (DCM). In this review, we summarize the mechanism of ferroptosis and especially its association with type 2 diabetes mellitus (T2DM).
铁死亡是一种新型的非凋亡性调节性细胞死亡（RCD）形式。其特征是铁依赖性脂质过氧化物积累，同时伴有氧化还原酶不足，尤其是谷胱甘肽过氧化物酶4（GPX4）。RAS选择性致死3（RSL3）、厄拉司丁和铁死亡诱导因子56（FIN56）通过靶向GPX4功能的不同方式诱导铁死亡。酰基辅酶A合成酶长链家族4（ACSL4）、溶血磷脂酰胆碱酰基转移酶3（LPCAT3）和脂氧合酶（LOXs）参与脂质过氧化物的产生。热休克蛋白家族B成员1（HSPB1）和核受体辅激活因子4（NCOA4）调节铁稳态，防止因细胞内铁浓度过高引起的铁死亡。铁死亡在我们体内普遍存在，因为它存在于生理和致病过程中。在糖尿病发病机制中，它参与葡萄糖刺激的胰岛素分泌（GSIS）受损和砷诱导的胰腺损伤。此外，铁与铁硫（Fe-S）簇相互影响，导致线粒体铁积累、更多活性氧（ROS）产生、内质网（ER）应激、胰岛素生物合成失败以及β细胞铁死亡。此外，铁死亡还参与糖尿病并发症如心肌缺血和糖尿病性心肌病（DCM）的发病机制。在本综述中，我们总结了铁死亡的机制，尤其是其与2型糖尿病（T2DM）的关联。
