Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis

Abstract

Regulated cell death (RCD) has a significant impact on development, tissue homeostasis, and the occurrence of various diseases. Among different forms of RCD, ferroptosis is considered as a type of reactive oxygen species (ROS)-dependent regulated necrosis. ROS can react with polyunsaturated fatty acids (PUFAs) of the lipid (L) membrane via the formation of a lipid radical L• and induce lipid peroxidation to form L-ROS. Ferroptosis is triggered by an imbalance between lipid hydroperoxide (LOOH) detoxification and iron-dependent L-ROS accumulation. Intracellular iron accumulation and lipid peroxidation are two central biochemical events leading to ferroptosis. Organelles, including mitochondria and lysosomes are involved in the regulation of iron metabolism and redox imbalance in ferroptosis. In this review, we will provide an overview of lipid peroxidation, as well as key components involved in the ferroptotic cascade. The main mechanism that reduces ROS is the redox ability of glutathione (GSH). GSH, a tripeptide that includes glutamic acid, cysteine, and glycine, acts as an antioxidant and is the substrate of glutathione peroxidase 4 (GPX4), which is then converted into oxidized glutathione (GSSG). Increasing the expression of GSH can inhibit ferroptosis. We highlight the role of the xc- GSH-GPX4 pathway as the main pathway to regulate ferroptosis. The system xc-, composed of subunit solute carrier family members (SLC7A11 and SLC3A2), mediates the exchange of cystine and glutamate across the plasma membrane to synthesize GSH. Accumulating evidence indicates that ferroptosis requires the autophagy machinery for its execution. Ferritinophagy is used to describe the removal of the major iron storage protein ferritin by the autophagy machinery. Nuclear receptor coactivator 4 (NCOA4) is a cytosolic autophagy receptor used to bind ferritin for subsequent degradation by ferritinophagy. During ferritinophagy, stored iron released becomes available for biosynthetic pathways. The dysfunctional ferroptotic response is implicated in a variety of pathological conditions. Ferroptosis inducers or inhibitors targeting redox- or iron metabolism-related proteins and signal transduction have been developed. The simultaneous detection of intracellular and extracellular markers may help diagnose and treat diseases related to ferroptotic damage.

Lithocholic Acid Alleviates Deoxynivalenol-Induced Inflammation and Oxidative Stress via PPARγ-Mediated Epigenetically Transcriptional Reprogramming in Porcine Intestinal Epithelial Cells

“…It is well established that elevated ROS leads to the accumulation of malondialdehyde (MDA), the end product of lipid peroxidation, causing cytotoxicity and damage. 37 Consistent with the ROS levels, LCA also reduced DONincreased MDA concentrations (Figure 2B). Second, analysis of the RNA-seq data set revealed that genes involved in antioxidation were downregulated during DON exposure, while the expression of oxidative genes was upregulated (Figure 2C).…”

“…First, LCA ameliorated the DON-elevated ROS levels in IPI-2I were measured (Figure A). It is well established that elevated ROS leads to the accumulation of malondialdehyde (MDA), the end product of lipid peroxidation, causing cytotoxicity and damage . Consistent with the ROS levels, LCA also reduced DON-increased MDA concentrations (Figure B).…”

Identification and Validation of Potential Ferroptosis-Related Genes in Glucocorticoid-Induced Osteonecrosis of the Femoral Head

“…ROS are produced by healthy cells in a highly regulated fashion in order to maintain intracellular redox homeostasis [ 32 ]. Oxidative stress can be described as an imbalance between the production of oxidant species and the antioxidant defenses, which may affect cellular redox homeostasis leading to molecular alterations and thus resulting in cell damage [ 33 ]. In addition, several recent studies have shown that the overproduction of ROS, disruption of the antioxidant stress system and production of oxidative DNA are important mechanisms of osteoblast apoptosis and osteoclastogenesis [ 34 , 35 ].…”

Disruption of lipid metabolism to induce ferroptosis using multifunctional fibrate-Pt(iv) prodrugs for cancer treatment

“…5,67 The ferritin heavy chain (FTH1) can catalyze the oxidation of Fe 2+ to Fe 3+ , reducing the participation of Fe 2+ in Fenton reactions, decreasing ROS production, and reducing free radical damage to cells and tissues. 68 Therefore, FTH1 expression can inhibit cell ferroptosis by reducing the Fe 2+ content. As shown in Fig.…”