Ferroptosis in Liver Diseases: An Overview

Abstract

Ferroptosis is an iron-dependent form of cell death characterized by intracellular lipid peroxide accumulation and redox imbalance. Ferroptosis shows specific biological and morphological features when compared to the other cell death patterns. The loss of lipid peroxide repair activity by glutathione peroxidase 4 (GPX4), the presence of redox-active iron and the oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids are considered as distinct fingerprints of ferroptosis. Several pathways, including amino acid and iron metabolism, ferritinophagy, cell adhesion, p53, Keap1/Nrf2 and phospholipid biosynthesis, can modify susceptibility to ferroptosis. Through the decades, various diseases, including acute kidney injury; cancer; ischemia–reperfusion injury; and cardiovascular, neurodegenerative and hepatic disorders, have been associated with ferroptosis. In this review, we provide a comprehensive analysis of the main biological and biochemical mechanisms of ferroptosis and an overview of chemicals used as inducers and inhibitors. Then, we report the contribution of ferroptosis to the spectrum of liver diseases, acute or chronic. Finally, we discuss the use of ferroptosis as a therapeutic approach against hepatocellular carcinoma, the most common form of primary liver cancer.

Iron Metabolism and Ferroptosis in Epilepsy

“…Meanwhile, O 2can bind hydrogen ions to produce H 2 O 2 . (Capelletti et al, 2020). This process prevents the formation and accumulation of iron-dependent lipid ROS.…”

“…During ferroptosis, ROS are produced from the Fenton reaction, which is a process of producing hydroxide (OH − ) and hydroxyl (OH • ) by the reaction between Fe 2+ and H 2 O 2 (Mittler, 2017). Moreover, The Haber-Weiss cycle showed that Fe 3+ is reduced to Fe 2+ through the reaction with superoxide (O 2− ), and Fe 2+ reacts with H 2 O 2 to form OH • , OH − , and Fe 3+ (Capelletti et al, 2020). Thus, Fe 2+ is conducive to the production of ROS and promotes lipid peroxidation, thus inducing ferroptosis.…”

“…− is inhibited, the production of GSH is decreased and the level of ROS and lipid peroxidation is increased, thereby leading to the occurrence of ferroptosis (Capelletti et al, 2020).…”

“…GSH is also a substrate for GPX4, which converts GSH to GSSG. Adjusting the GSSG/GSH ratio affects ROS levels (Bjørklund et al, 2020;Capelletti et al, 2020). However, in epilepsy, the GSH level was decreased, and the ROS level was increased.…”

“…Moreover, the silencing of IREB2, as the iron metabolism master regulator, also decreases the sensitivity of cells to ferroptosis (Dixon et al, 2012). IREB2 silencing alters many genes in iron metabolism: TRFC, FTH1, and FTL (Capelletti et al, 2020). Some studies have confirmed that HSBP1 reduces iron levels by inhibiting TFR1 expression.…”