Recent progress in ferroptosis: inducers and inhibitors

Abstract

Ferroptosis is a new iron-dependent form of programmed cell death characterized by iron accumulation and lipid peroxidation. In recent years, ferroptosis has garnered enormous interest in disease treatment research communities in pursuit to reveal the mechanism and key targets of ferroptosis because ferroptosis is closely related to the pathophysiological processes of many diseases. Recent studies have shown some key targets, such as glutathione peroxidase 4 (GPX4) and System Xc^-, and several inducers and inhibitors have been developed to regulate these key targets. With the emergence of new ferroptosis targets, studies on inducers and inhibitors have made new developments. The selection and use of inducers and inhibitors are very important for related work. This paper briefly introduces important regulatory targets in the ferroptosis metabolic pathway, lists and categorizes commonly used and recently developed inducers and inhibitors, and discusses their medical application. The paper ends of with potential future research direction for ferroptosis.

Fig. 1. Ferroptosis regulators associated with iron metabolism.

Ferroptosis depends on iron ion because it can produce lipid ROS through Fenton reaction. Therefore, substances that regulate iron ions, such as iron chelators and regulators of related proteins or organelles, also function in the regulation of ferroptosis. Additionally, many nanoparticles based on other metal ions are also able to induce ferroptosis by effecting iron ions or directly generating ROS. TMZ temozolomide, DMT1 divalent metal transporter 1, Fe ferrum (iron), CPX ciclopirox olamine, DFO deferoxamine, DFP deferiprone, DFX deferasirox, RSL5 RAS synthetic lethal 5, DIDS 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid, VDACs voltage-dependent anion channels, C’ dots Cornell prime dots, SPION superparamagnetic iron oxide nanoparticles, CPMNS hybrid CoMoO4-phosphomolybdic acid nanosheets, ROS reactive oxygen species.

Fig. 2. Substances that affect ferroptosis by regulating lipid metabolism.

Lipid ROS accumulation caused by lipid peroxidation plays an important role in ferroptosis while antioxidants can prevent ferroptosis. Two of the important enzymes in lipid metabolism are ACSL4 and ALOX15, thus their regulators affect the process of ferroptosis. NEAT1 nuclear enriched transcript 1, Fer-1 ferrostatin-1, ACSL4 acyl-CoA synthetase long chain family member 4, ALOX15 arachidonate lipoxygenase 15, PUFAs polyunsaturated fatty acids, AA arachidonic acid, AA-CoA acyl-CoA, PMC photosynthetic microcapsule.

Fig. 3. Regulators of ferroptosis through GSH/GPX4 axis.

GSH is a crucial reductant, whose production involves amino acid transporters and a variety of enzymes, such as System Xc⁻ and GPX4, which are important targets for regulating ferroptosis. In addition, in specific cells like M1 tumor-associated macrophages, iNOS can catalyze the production of another reductant NO to inhibit ferroptosis. DKK1 dickkopf-1, OTUB1 ovarian tumor domain-containing ubiquitin aldehyde binding protein 1, Glu glutamate, MEII morpholine erastin II, PE piperazine erastin, AE aldehyde erastin, β-ME β-Mercaptoethanol, SAS sulfasalazine, BAP1 BRCA1-associated protein 1, BSO buthionine sulfoximine, ChA CQDs chlorogenic acid carbon quantum dots, LDL-DHA low-density lipoprotein-docosahexaenoic acid nanoparticles, GCL glutamate–cysteine ligase, GSH glutathione, DEPE1 dipeptidase-1, GPX4 glutathione peroxidase 4, CDDO bardoxolone, HSP90 heat shock protein 90, Se selenium, TFAP2c transcription factor activating protein 2 gamma, Sp1 specificity protein 1, iNOS inducible nitric oxide synthase, RSL3 RAS synthetic lethal 3, FIN56 ferroptosis inducing 56.

Fig. 4. FSP1/CoQ and other metabolism pathways involved in ferroptosis.

FSP1 can catalyze the transition from VK to VKH₂ and CoQ to CoQH₂ also catalyzed by DHODH to affect the process of ferroptosis. Thus, regulators targeting these two proteins such as miR-672-3p and brequinar can regulate ferroptosis. In addition, TCA cycle promoted by glutaminolysis can contribute to lipid peroxidation in the case of cystine deficiency to inhibit ferroptosis. Moreover, the proteasome regulates ferroptosis in a temporarily undefined manner. α-KG α-ketoglutarate dehydrogenase complex, TCA cycle tricarboxylic acid cycle, DHODH dihydroorotate dehydrogenase, CoQ coenzyme Q, HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase, SQS squalene synthase, FIN56 ferroptosis inducing 56, FSP1 ferroptosis suppressor protein 1, NAD(P)H nicotinamide adenine dinucleotide phosphate, VK vitamin K, NFE2L1 nuclear factor erythroid-2, like-1.