Ferroptosis inhibitors: past, present and future

Abstract

Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed the mechanisms of its formation and continue to explore effective inhibitors of ferroptosis in disease. Recent studies have shown a correlation between ferroptosis and the pathological mechanisms of neurodegenerative diseases, as well as diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for the treatment of ferroptosis-mediated diseases. This article specifically describes the metabolic pathways of ferroptosis and summarizes the reported mechanisms of action of natural and synthetic small molecule inhibitors of ferroptosis and their efficacy in disease. The paper also describes ferroptosis treatments such as gene therapy, cell therapy, and nanotechnology, and summarises the challenges encountered in the clinical translation of ferroptosis inhibitors. Finally, the relationship between ferroptosis and other modes of cell death is discussed, hopefully paving the way for future drug design and discovery.

Keywords: antioxidants system; clinical translation; ferroptosis; inhibitors; iron metabolism; lipid metabolism.

FIGURE 1

Iron metabolism pathways and their associated inhibitors of ferroptosis Serum Transferrin (TF); The membrane protein Transferrin Receptor1 (TFR1); Six-Transmembrane Epithelial Antigen of Prostate 3 (STEAP3); Ceruloplasmin (CP); Divalent Metal Transporter 1 (DMT1); Polyunsaturated fatty acids (PUFAs); Phosphatidyl Ethanolamine-Polyunsaturated Fatty Acids (PE-PUFA); Lipoxygenase (LOX); Ferritin; Membrane iron transport protein 1 (Ferroportin1, FPN1); Nuclear receptor coactivator 4 (NCOA4); Lipid hydroperoxide (PL-PUFA-OOH); Promimin 2.

FIGURE 2

Lipid metabolic pathways and their associated inhibitors of ferroptosis. Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4); Recombinant Solute Carrier Family 3, Member 2 (SLC3A2); Malondialdehyde (MDA); 4-hydroxynonenal (4HNE); Cytochrome P450 oxidoreductase (POR); Flavin mononucleotide (FMN); Flavin adenine dinucleotide (FAD).

FIGURE 3

Antioxidant pathways and their associated inhibitors of ferroptosis Recombinant Solute Carrier Family 7, Member 11 (SLC7A11); Recombinant Solute Carrier Family 3, Member 2 (SLC3A2); Glutamate-cysteine ligase (GCL); Glutathione Synthase (GSS); Glutathione (GSH); Glutathione Peroxidase 4 (GPX4); Oxidized glutathione, GSSG; Glutamic acid (Glu); Cystine (Cys); Nuclear factor E2-related factor 2 (Nrf2); p53 (tumor suppressor); Recombinant Kelch-like ECH Associated Protein 1 (Keap1); Antioxidant response element (ARE); Heme oxygenase-1 (HO-1); Ferroptosis Inhibitory Protein 1 (FSP1); Coenzyme Q₁₀ (CoQ₁₀); Panthenol (CoQ₁₀H₂); Nicotinamide Adenine Dinucleotide Phosphate (NADPH); Dihydroorotate dehydrogenase (DHODH); GTP Cyclohydrolase-1 (GCH1); Tetrahydrobiopterin (BH4); GTP Cyclohydrolase-1-Tetrahydrobiopterin (GCH1-BH4); Mevalonate (MVA); Heat Shock Protein Beta-1 (HSPB1); Heat shock factor (HSF1); 6-hydroxy-FAD; p53-iPLA2β axis; p21; Acetyl-coenzyme A (Acetyl-CoA).