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.

Keywords: cell death; ferroptosis; iron metabolism; liver.

Figure 1

This figure summarizes the regulatory core of ferroptosis, approximately divided into three axes. The first axis is represented in the middle. It includes the GSH/GPX4, sulfur transfer and p53 pathways. The second axis (right part of theF) consists of the iron metabolism pathway, including IREB2 related to ferritin metabolism, the regulation of ATG5-ATG7-NCOA4 pathway and the p62-Keap1-Nrf2 regulatory pathway. These elements can influence the concentration of intracellular iron, mandatory for the development of ferroptosis. On the left, the third axis implies that lipid metabolism p53-spermidine/spermine N1-acetyltransferase 1 (SAT1)-ALOX15, ACSL4, LPCAT3, etc. impact on fatty acids regulation and ferroptosis [3]. Finally, mitochondria are also involved, since VDACs (voltage-dependent anion channels) are inhibited by erastin. In parallel, the independent pathway ferroptosis suppressor protein 1-coenzyme Q10 (FSP-1-CoQ10) acts with GSH/GPX4 to contrast lipid peroxidation [3].

Figure 2

Oxidized GSH (GSSG) is exported from the cell via the MRP/ABCC transporter and hydrolyzed by GGT and dipeptidase to Gly, Glu and Cys₂, thus contributing to the extracellular amino γ-glutamylcysteine acid pool. Specific amino acid transporters (AT1 and AT2) internalize Gly and Glu, while Cys₂ is taken up by system X_c⁻ [11]. Once in the cell, Cys₂ is reduced to Cys and combined with Glu to generate γGlu-Cys [11]. The addition of Gly to the dipeptide catalyzes the formation of GSH, a cofactor of GPX4. The box on the bottom left indicates the proteins involved.

Figure 3

Exogenous ferroptosis inducers [49].

Figure 4

Ferroptosis inhibitors [52].

Figure 5

Etiologic factors and the central role of oxidative stress in the development of hepatic diseases. Several factors (e.g., HBV/HCV infection, inadequate alcohol or drug consumption, metabolic or genetic diseases, and I-R injury (1)) may trigger CLD or ALD (2) in the liver, promoting iron accumulation. This supports pro-oxidative state triggering protein and DNA damage and lipid peroxidation (3). The instauration of hepatocyte oxidative stress conditions results in inflammation (4–5), which favors liver fibrosis (6) and cirrhosis (7), and it may lead to hepatocellular carcinoma (8). Numbers (1–8) were added to indicate the path to follow in reading the image. HSC, hematopoietic stem cells; TGFβ, transforming growth factor-beta.