Ferroptosis: action and mechanism of chemical/drug-induced liver injury

Abstract

Drug-induced liver injury (DILI) is characterized by hepatocyte injury, cholestasis injury, and mixed injury. The liver transplantation is required for serious clinical outcomes such as acute liver failure. Current studies have found that many mechanisms were involved in DILI, such as mitochondrial oxidative stress, apoptosis, necroptosis, autophagy, ferroptosis, etc. Ferroptosis occurs when hepatocytes die from iron-dependent lipid peroxidation and plays a key role in DILI. After entry into the liver, where some drugs or chemicals are metabolized, they convert into hepatotoxic substances, consume reduced glutathione (GSH), and decrease the reductive capacity of GSH-dependent GPX4, leading to redox imbalance in hepatocytes and increase of reactive oxygen species (ROS) and lipid peroxidation level, leading to the undermining of hepatocytes; some drugs facilitated the autophagy of ferritin, orchestrating the increased ion level and ferroptosis. The purpose of this review is to summarize the role of ferroptosis in chemical- or drug-induced liver injury (chemical/DILI) and how natural products inhibit ferroptosis to prevent chemical/DILI.

Keywords:

• Chemical or drug induced liver injury
• ferroptosis
• reactive oxygen species
• GPX4
• glutathione
• antitubercular agents

Authors contributions

Conceptualization, X.X. and D.C.W. Methodology, L.Z. and X.L.J. Resources, Q.A.X. and W.J. Writing—Original Draft Preparation, L.Z. and X.L.J. Writing—Review and Editing, D. Z. Supervision, S.S.H and J.C. Project Administration, X.X. and D.C.W. Funding Acquisition, X.X. and D.C.W. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Figure 1. Graphical interpretation to chemical/drug-induced ferroptosis during liver injury. The heterodimer System Xc⁻ (seen in cell membrane) consists of two subunits, SLC7A11 and SLC3A2. System Xc^—mediated ysteine uptake enhance the synthesis of subsequent GSH. GPX4 converts GSH to GSSG to reduce PLOOH and inhibit lipid peroxidation and protect cell from ferroptosis. TFR1 uptakes Fe³⁺ into cells, which is then reduced to Fe²⁺ by STEAP3. Ferritin degenerate through ferritinophagy and release Fe²⁺. The Fenton reaction mediated by Fe²⁺ produces a large amount of •OH to reinforce lipid peroxidation. Under the catalytic intervention of ACSL4 and LPCAT3, PUFA was oxidized to PUFA-PE; under the action of ALOXs, lipid peroxidation occurs in PUFA-PE. Reactive oxygen species (ROS) overproduction and failure to eliminate lipid peroxides (LPO) are key causes of ferroptosis.

Figure 2. Cytoprotective agents against in drugs/chemicals–induced ferroptosis during liver injury. Rifampicin expedites ferritinophagy and increases the concentration of Fe²⁺ in labile iron pool (LIP), which accelerates lipid peroxidation through the Fenton reaction, thus facilitating ferroptosis. While silibinin inhibits ferritinophagy in ethanol-induced ferroptosis, silibinin could also evoke the autophagy of damaged mitochondria which reduces the production of ROS and lipid peroxides. APAP, ethanol, CCl₄ and pirarubicin reduce antioxidant capacity (GSH, GPX4 activity) which is against lipid peroxidation and then induce ferroptosis. Verbenalin and astaxanthin can upregulate GSH and protect hepatocytes from ferroptosis caused by decreased GSH. Astaxanthin could also ameliorate ferroptosis by upregulating SLC7A11 and FTH1 to strengthen the biosynthesis of GSH. Schisandrin B and baicalein upregulate Nrf2 and GPX4 to inhibit ferroptosis. Bicyclol and baicalein protect hepatocytes from ferroptosis by lessening lipid metabolic enzyme ACSL4 and ALOX, and abating lipid peroxidation. Moreover, baicalein also inhibits NF-κB-mediated cytokines (TNF-α, IL-1β and IL-6) to alleviate liver injury.

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China [No. 31772709] and the Hubei Natural Science Foundation [2015CFB316] of China.