Emerging roles of ferroptosis in liver pathophysiology
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Online ISSN 1976-3786 Print ISSN 0253-6269
REVIEW
Emerging roles of ferroptosis in liver pathophysiology Kyu Min Kim1 · Sam Seok Cho1 · Sung Hwan Ki1
Received: 6 August 2020 / Accepted: 13 October 2020 © The Pharmaceutical Society of Korea 2020
Abstract Ferroptosis is a widely recognized process of regulated cell death linking redox state, metabolism, and human health. It is considered a defense mechanism against extensive lipid peroxidation, a complex process that may disrupt the membrane integrity, eventually leading to toxic cellular injury. Ferroptosis is controlled by iron, reactive oxygen species, and polyunsaturated fatty acids. Accumulating evidence has addressed that ferroptosis plays an unneglectable role in regulating the development and progression of multiple pathologies of the liver, including hepatocellular carcinoma, liver fibrosis, nonalcoholic steatosis, hepatic ischemia–reperfusion injury, and liver failure. This review may increase our understating of the cellular and molecular mechanisms of liver disease progression and establish the foundation of strategies for pharmacological intervention. Keywords Ferroptosis · Liver · Iron · ROS · Cell death
Introduction Ferroptosis is an oxidative, iron-dependent, non-apoptotic, peroxidation-driven form of regulated cell death, and its biochemical, morphological, and genetic characteristics are distinct from apoptosis, necrosis, autophagy, and other types of cell death (Yagoda et al. 2007; Yang and Stockwell 2008; Dixon et al. 2012; Fatokun et al. 2014). Apoptosis is mediated by pro-death molecules such as BCL2-associated X protein, whereas ferroptosis is initiated by glutathione (GSH) * Sung Hwan Ki [email protected] 1
depletion or glutathione peroxidase 4 (GPX4) inactivation (Dixon et al. 2012; Yang et al. 2014). Hallmarks of apoptosis, such as cleavage of poly (ADP ribose) polymerase 1 by caspase-3 or release of cytochrome c from mitochondria, are not observed during ferroptosis (Yagoda et al. 2007; Yang et al. 2014). Moreover, there are distinguishable morphological characteristics of mitochondria during ferroptosis, which include the following: smaller than normal mitochondria with condensed membrane density, absent or reduced crista, and rupture of the outer membrane (Yagoda et al. 2007; Dixon et al. 2012; Xie et al. 2016). Additionally, ferroptosis is characterized by an iron-mediated excessive peroxidation of polyunsaturated fatty acids (PUFAs), including phospholipids present in cell membranes (Dixon et al. 2015). Treatment with iron chelators (deferoxamine) or antioxidants (vitamin E, ferrostatin-1, liproxstatin-1) can reverse the lipid peroxidation of ferroptosis (Dixon et al. 2012; Friedmann Angeli et al. 2014). Although ferroptosis is considered as an essential mechanism for sustaining cell survival, some cells are extremely susceptible to ferroptotic cell death (Friedmann Angeli et al. 2019). Recently, ferroptosis has gained a lot of interest, especially in view of the modulation of genes involved in ferroptosis or introduction of
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