Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the chronic liver disease with the highest incidence throughout the world, but its pathogenesis has not been fully elucidated. Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation. Abnormal iron metabolism, lipid peroxidation, and accumulation of polyunsaturated fatty acid phospholipids (PUFA-PLs) can all trigger ferroptosis. Emerging evidence indicates that ferroptosis plays a critical role in the pathological progression of NAFLD. Because the liver is the main organ for iron storage and lipid metabolism, ferroptosis is an ideal target for liver diseases. Inhibiting ferroptosis may become a new therapeutic strategy for the treatment of NAFLD. In this article, we describe the role of ferroptosis in the progression of NAFLD and its related mechanisms. This review will highlight further directions for the treatment of NAFLD and the selection of corresponding drugs that target ferroptosis.
Highlights
Non-alcoholic fatty liver disease (NAFLD) has become the chronic liver disease with the highest incidence throughout the world, but its pathogenesis has not been fully elucidated
There is an article studying the significance of microrna in the pathogenesis of fructose-induced NAFLD, and it found that fructose-induced oxidative damage can induce ferroptosis and that miR-33 can be used as a serological biomarker for fructoseinduced NAFLD [82]
Ferroptosis plays an important role in liver pathophysiology, and it plays a key role in triggering the development of NAFLD to nonalcoholic steatohepatitis (NASH)
Summary
The term “ferroptosis” was first proposed by Dixon et al, in 2012, and it was used to describe a non-apoptotic form of cell death caused by erastin-induced iron-dependent lipid peroxide accumulation [8]. The main morphological characteristics of ferroptosis are the shrinkage of cell volume, the decrease of mitochondrial cristae, and the increase of mitochondrial membrane density without typical apoptotic or necrotic manifestation [8]. GPX4 is the main enzyme that protects the cell membrane against peroxidative damage [30,31], and either its direct or indirect inactivation or an increase in the unstable iron pool will induce the occurrence of ferroptosis [8]. Iron chelator (deferoxamine) and some small molecule compounds (such as ferrostatin-1 (Fer-1) and lipoxstatin-1 (Lip-1)) can reverse the lipid peroxidation caused by ferroptosis [8,29]. Abnormal iron metabolism and lipid peroxidation may be the main factors that cause ferroptosis, and the system Xc− /GSH/GPX4 axis plays a crucial role in this process.
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