Abstract
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 β-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).
Highlights
Ferroptosis, which was first defined in 2012, is a form of nonapoptotic regulated cell death (RCD) because it takes place without caspases, a family of cysteine proteases cleaving specific intracellular substrates leading to apoptosis [1,2,3]
Ferroptosis is dependent on intracellular iron instead of any other metals, and it is morphologically and biochemically different from other types of RCD such as receptorinteracting protein kinase 1- (RIPK1-) dependent necroptosis and apoptosis-inducing factor 1-dependent parthanatos [5, 6]
Inadequate supply of cystine due to an inhibition of the xc− system leads to decreased production of cysteine and the depletion of GSH, which will eventually suppress the normal activity of glutathione peroxidase 4 (GPX4) in preventing ferroptosis [27]
Summary
Ferroptosis, which was first defined in 2012, is a form of nonapoptotic regulated cell death (RCD) because it takes place without caspases, a family of cysteine proteases cleaving specific intracellular substrates leading to apoptosis [1,2,3]. Ferroptosis is dependent on intracellular iron instead of any other metals, and it is morphologically and biochemically different from other types of RCD such as receptorinteracting protein kinase 1- (RIPK1-) dependent necroptosis (a regulated form of necrosis) and apoptosis-inducing factor 1-dependent parthanatos [5, 6]. It does not involve the key factors of necroptosis such as MLKL, RIPK1, and RIPK3 [7]. P53 can suppress ferroptosis through the DPP4-dependent pathway [26]
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