Abstract
Ferroptosis is a newly identified form of regulated cell death driven by iron-dependent phospholipid peroxidation and oxidative stress. Ferroptosis has distinct biological and morphology characteristics, such as shrunken mitochondria when compared to other known regulated cell deaths. The regulation of ferroptosis includes different molecular mechanisms and multiple cellular metabolic pathways, including glutathione/glutathione peroxidase 4(GPX4) signaling pathways, which are involved in the amino acid metabolism and the activation of GPX4; iron metabolic signaling pathways, which are involved in the regulation of iron import/export and the storage/release of intracellular iron through iron-regulatory proteins (IRPs), and lipid metabolic signaling pathways, which are involved in the metabolism of unsaturated fatty acids in cell membranes. Ferroptosis plays an essential role in the pathology of various kidneys diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), autosomal dominant polycystic kidney disease (ADPKD), and renal cell carcinoma (RCC). Targeting ferroptosis with its inducers/initiators and inhibitors can modulate the progression of kidney diseases in animal models. In this review, we discuss the characteristics of ferroptosis and the ferroptosis-based mechanisms, highlighting the potential role of the main ferroptosis-associated metabolic pathways in the treatment and prevention of various kidney diseases.
Highlights
Ferroptosis is distinct from apoptosis, necrosis, and autophagy, based on the criteria of morphology, biochemical, and genetic
We discussed the difference between ferroptosis and other regulated cell deaths, the signaling pathways involved in the regulation of ferroptosis, the role of ferroptosis in kidneys diseases, and the action of ferroptosis inhibitors in kidney diseases
There are still some concerns that need to be addressed, including the following: (1) ferroptosis is morphologically, biologically, and genetically distinct from other types of cell death, such as apoptosis, autophagy, and necrosis, growing evidence indicates that ferroptosis is closely intertwined with all other forms of cell death to build a network
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Iron metabolism includes iron cells from ferroptotic death, in that GSH is essential: (i) for the maintenance of the level of GPX4 through the exchange of glutamate and cystine via cystine/glutamate antiporter system Xc-, and (ii) for the functional activity of GPX4 to reduce lipid hydroperoxides (L-OOH) to lipid alcohols (L-OH), resulting in the prevention of the iron (Fe2+ )-dependent formation of toxic lipid ROS. GPX4 is one of eight well-known GSH peroxidases in mammals [12] and one of the most important and studied enzymes in the ferroptotic process It reduces complex hydroperoxides, including phospholipid hydroperoxides and cholesterol hydroperoxides to their corresponding counterparts, thereby interrupting the lipid peroxidation chain reaction [13]. A recent study showed that erastin inactivated GPX4 but could repress GPX4 expression by upregulating the expression of ATF3, in which ATF3 could repress the expression of GPX4 [15]
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