Targeting ferroptosis opens new avenues for the development of novel therapeutics

Abstract

Ferroptosis is an iron-dependent form of regulated cell death with distinct characteristics, including altered iron homeostasis, reduced defense against oxidative stress, and abnormal lipid peroxidation. Recent studies have provided compelling evidence supporting the notion that ferroptosis plays a key pathogenic role in many diseases such as various cancer types, neurodegenerative disease, diseases involving tissue and/or organ injury, and inflammatory and infectious diseases. Although the precise regulatory networks that underlie ferroptosis are largely unknown, particularly with respect to the initiation and progression of various diseases, ferroptosis is recognized as a bona fide target for the further development of treatment and prevention strategies. Over the past decade, considerable progress has been made in developing pharmacological agonists and antagonists for the treatment of these ferroptosis-related conditions. Here, we provide a detailed overview of our current knowledge regarding ferroptosis, its pathological roles, and its regulation during disease progression. Focusing on the use of chemical tools that target ferroptosis in preclinical studies, we also summarize recent advances in targeting ferroptosis across the growing spectrum of ferroptosis-associated pathogenic conditions. Finally, we discuss new challenges and opportunities for targeting ferroptosis as a potential strategy for treating ferroptosis-related diseases.

Fig. 1

Timeline of the identification and characterization of ferroptosis, and the underlying mechanisms. a, Timeline depicting the past, present, and future of ferroptosis. The first time period (1980–2012) ended with the term “ferroptosis” being coined by Dixon et al. in 2012. The present period (2012–2023) developed rapidly, with important details emerging such as the GCH1-BH₄ and DHODH-CoQ₁₀ pathways. The future (2023-?) is expected to bring numerous new applications for targeting ferroptosis. b, Three pathways mediate ferroptosis, including iron metabolism, redox, and lipid metabolism. Dysregulation of oxidative-reductive systems, iron metabolism, and/or peroxidation of PUFAs can induce ferroptosis. ACSL4, acyl-CoA synthetase long-chain family member 4; BH₄, tetrahydrobiopterin; CBS, cystathionine beta-synthase; CD36, cluster differentiation 36; CoQ₁₀, coenzyme Q₁₀; CTH, cystathionine gamma-lyase; DHODH, dihydroorotate dehydrogenase; DMT1, proton-coupled divalent metal ion transporter 1; FPN, ferroportin; FSP1, ferroptosis suppressor protein 1; GCH1, GTP cyclohydrolase 1; GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; HO-1, heme oxygenase 1; Keap1, Kelch-like ECH-associated protein 1; LOX, lipoxygenase; LPCAT, lysophosphatidylcholine acyltransferase; MUFA, monounsaturated fatty acid; NCOA4, nuclear receptor coactivator 4; Nrf2, nuclear factor erythroid 2-related factor 2; PL-PUFA, phospholipid-containing polyunsaturated fatty acid; PUFA, polyunsaturated fatty acid; RNF217, E3 ubiquitin protein ligase RNF217; SCD1, stearoyl-coenzyme A desaturase 1; SLC, solute carrier family; SQS, squalene synthase; STEAP, 6-transmembrane epithelial antigen of the prostate metalloreductase family; TF, transferrin; TFR1, transferrin receptor protein 1; TRPML, lysosomal cation channel mucolipin. Created with BioRender.com

Fig. 2

Ferroptosis-related diseases that can present throughout the human lifespan. As we age, iron levels in the body accumulate, inducing ferroptosis and increasing our susceptibility to hypoxic-ischemic brain damage, organ injury‒related diseases, and neurodegenerative diseases. Reduced ferroptosis can cause various forms of cancers in all stages of life. NAFLD non-alcoholic fatty liver disease, NASH non-alcoholic steatohepatitis. Created with BioRender.com

Fig. 3

Targeting ferroptosis in iron metabolism. a Overview of systemic iron homeostasis. Labile iron binds to transferrin (TF) in the blood, and senescent erythrocytes are phagocytized by macrophages, releasing iron ions back into the circulation. The primary regulatory mechanism of iron homeostasis involves liver-derived hepcidin, which controls the cellular export of iron via ferroportin (FPN). b Overview of the various processes that involve ferritin under iron-deficient and iron-sufficient conditions. When cellular iron is sufficient, ferritin stores iron. Under iron-deficient conditions, ferritin undergoes NCOA4-mediated ferritinophagy and releases iron. c The active labile iron pool can be used either directly for incorporation into iron-containing proteins or transported into the mitochondria. d Overview of iron transporters in the plasma membrane and in lysosomes. Molecules in the pink and green text boxes are inhibitors or activators, respectively, of the pathways that regulate iron metabolism and suppress or trigger, respectively, ferroptosis. ALAS 5-amibolevulinic acid synthase, DMT1 proton-coupled divalent metal ion transporter 1, EPO erythropoietin; FLVCR1b, FLVCR heme transporter 1b, HERC2 HECT and RLD domain containing E3 ubiquitin protein ligase 2, HO-1 heme oxygenase 1, LIP labile iron pool, MFRN mitoferrin, NCOA4 nuclear receptor coactivator 4, PCBP poly(rC)-binding protein, RNF217 E3 ubiquitin protein ligase RNF217, SLC solute carrier family, STEAP 6-transmembrane epithelial antigen of the prostate metalloreductase family, TFR1 transferrin receptor protein 1, TRPML lysosomal cation channel mucolipin. Created with BioRender.com

Fig. 4

Targeting ferroptosis in reductive-oxidative pathways. Ferroptosis is tightly associated with levels of reactive oxygen species (ROS); therefore, homeostasis of the cellular reductive-oxidative response is important for regulating ferroptosis. The system Xc^–-GSH-GPX4 pathway is a major ROS scavenger, and numerous molecules are designed to target the components involved in this pathway in order to modulate ferroptosis. The recently identified FSP1-CoQ₁₀-NAD(P)H pathway and mitochondrial DHODH-mediated pathway are also potential targets for modulating ferroptosis. Moreover, NRF2 respond to cellular oxidative status by activating the transcription of genes involved in reductive-oxidative responses. Thus, targeting the KEAP1-NRF2 axis may be a viable strategy for modulating ferroptosis. Molecules listed in pink and green text boxes inhibit or induce, respectively, the indicated reductive-oxidative regulatory pathways, thereby suppressing or triggering, respectively, ferroptosis. CBS cystathionine beta-synthase, CoQ₁₀ coenzyme Q₁₀, CTH cystathionine gamma-lyase, DHODH dihydroorotate dehydrogenase, DPP4 dipeptidyl peptidase 4, FMN flavin mononucleotide, FMNH₂ reduced flavin mononucleotide, FSP1 ferroptosis suppressor protein 1, GCL glutamate-cysteine ligase, GLS glutaminase, GLUD1 glutamate dehydrogenase 1, GPX4 glutathione peroxidase 4, GSH glutathione, GSR glutathione disulfide reductase, GSS glutathione synthetase, GSSG glutathione disulfide, KEAP1 Kelch-like ECH-associated protein 1, NOX1 NADPH oxidase 1, NRF2 nuclear factor erythroid 2-related factor 2, SLC solute carrier family, TCA tricarboxylic acid, TXNRD thioredoxin reductase. Created with BioRender.com

Fig. 5

Targeting ferroptosis in lipid metabolism pathways. Cellular fatty acids are taken up by CD36 and FABPs, and stored in the free fatty acid (FFA) pool. Cells can also take up cholesterol via the LDLR or produce it from acetyl-CoA. These fatty acids can then be elongated to form long fatty acids and can be unsaturated to form monounsaturated fatty acids (MUFAs) or polyunsaturated fatty acids (PUFAs). MUFAs can be converted to PUFAs via the activity of FADS. ACSL4 and LPCAT3 are key enzymes that promote the incorporation of PUFAs into phospholipids (PLs) to form PL-PUFAs and induce ferroptosis. Molecules in the pink and green text boxes inhibit or induce, respectively, the indicated components in the lipid metabolism regulatory pathways, thereby suppressing or triggering, respectively, ferroptosis. ACC acetyl-CoA carboxylase, ACSL4 acyl-CoA synthetase long-chain family member 4, ALOX arachidonate lipoxygenase, CD36 cluster differentiation 36, FABP fatty acid binding protein, FADS fatty acid desaturase, FASN fatty acid synthase, HMG-CoA 3-hydroxy-3-methylglutaryl-CoA, HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase, LDLR low density lipoprotein receptor, LPCAT3 lysophosphatidylcholine acyltransferase 3, PEBP1 phosphatidylethanolamine binding protein 1, SCD1 stearoyl-coenzyme A desaturase 1, SQLE squalene epoxidase, SQS squalene synthase. Created with BioRender.com

Fig. 6

Five strategies for developing nanoparticles to target ferroptosis. Five principal strategies have been used to design nanoparticles to modulate ferroptosis. In all five strategies, nanoparticles contain compounds that either directly modulate ferroptosis or affect signaling pathways that modulate ferroptosis. GSH, glutathione; GPX4, glutathione peroxidase 4; ROS, reactive oxygen species. Created with BioRender.com