Mechanisms and therapeutic targets of ferroptosis: Implications for nanomedicine design

Abstract

Ferroptosis is a nonapoptotic form of cell death and differs considerably from the well-known forms of cell death in terms of cell morphology, genetics, and biochemistry. The three primary pathways for cell ferroptosis are system Xc^-/glutathione peroxidase 4 (GPX4), lipid metabolism, and ferric metabolism. Since the discovery of ferroptosis, mounting evidence has revealed its critical regulatory role in several diseases, especially as a novel potential target for cancer therapy, thereby attracting increasing attention in the fields of tumor biology and anti-tumor therapy. Accordingly, broad prospects exist for identifying ferroptosis as a potential therapeutic target. In this review, we aimed to systematically summarize the activation and defense mechanisms of ferroptosis, highlight the therapeutic targets, and discuss the design of nanomedicines for ferroptosis regulation. In addition, we opted to present the advantages and disadvantages of current ferroptosis research and provide an optimistic vision of future directions in related fields. Overall, we aim to provide new ideas for further ferroptosis research and inspire new strategies for disease diagnosis and treatment.

Keywords: Ferroptosis; Mechanisms; Nanomedicines; Therapeutic targets.

Graphical abstract

Fig. 1

Annual growth in the number of published papers on ferroptosis (Statistics from the Web of Science; access date: March 20, 2023).

Fig. 2

Typical morphological images of the different cell death pathways: (A) ferroptosis [44], (B) apoptosis [45], (C) autophagy [46], (D) necroptosis [47], and (E) pyroptosis [48]. CuB: cucurbitacin B; NC: blank control group; BBR: berberine; DDP: cisplatin; T-DM1: trastuzumab emtansine. Reprinted from Refs. [[44], [45], [46], [47], [48]] with permission.

Fig. 3

The system Xc⁻/GPX4 pathway is used to activate ferroptosis. SLC3A2: solute carrier family 3 member 2; SLC7A11: solute carrier family 7 member 11; NADP⁺: oxidized form of nicotinamide adenine dinucleotide phosphate (NADPH); GCL: glutamate cysteine ligase; GSS: glutathione (GSH) synthetase; GPX4: GSH peroxidase 4; GSSG: oxidized GSH; LOH: lipid alcohol; LOOH: lipid hydroperoxide; ROS: reactive oxygen species; PDPT: palladium pyrithione complex.

Fig. 4

Mechanisms are used to defend ferroptosis. SLC7A11: solute carrier family 7 member 11; NADP⁺: oxidized form of nicotinamide adenine dinucleotide phosphate (NADPH); GCL: glutamic cysteine ligase; GSS: glutathione (GSH) synthetase; LOOH: lipid hydroperoxide; GPX4: GSH peroxidase 4; GSSG: oxidized GSH; LOH: lipid alcohol; PDPT: palladium pyrithione complex; FSP1: ferroptosis suppressor protein 1; CoQ10: coenzyme Q10; CoQH2: ubiquinol; BQR: brequinar; DHO: dihydroorotate; DHODH: DHO dehydrogenase; BH4: tetrahydrobiopterin; GCH1: guanosine triphosphate (GTP) cyclohydrolase 1.

Fig. 5

Nanomedicine design based on cystine/glutathione (GSH)/GSH peroxidase 4 (GPX4) mechanism applied in cancer and inflammatory bowel disease (IBD). (A) Schematic illustration of the design of maltose-poly(ethylene glycol) (PEG)-azobenzene@RSL3 micelles and the mechanisms for triggering ferroptosis after entering the HepG2 cells [120]. (B) Schematic illustration of the preparation processes and the mechanisms of an oral nano-antioxidant encapsulated curcumin (Cur) and nanoceria (CeO₂) (Ce) to mannose modified chitosan (MCS) (Cur-Ce@MCS) for the treatment of IBD [101]. RSL3: a GPX4 inhibitor; Trx: thioredoxin; Trx (SS): oxidized Trx; TrxR: Trx reductase; Trx(SH)₂: reduced Trx; NADPH: nicotinamide adenine dinucleotide phosphate; NADP⁺: oxidized form of NADPH; GSSG: oxidized GSH; GR: GSH reductase; PE-AA-OH: hydroxy-arachidonoyl phosphatidylethanolamine; PE-AA-OOH: hydroperoxy-arachidonoyl phosphatidylethanolamine; GLUT: glucose transporter; CS: chitosan; HSA: human serum albumin; ROS: reactive oxygen species; M1: macrophages M1 phenotype; IL-1β: interleukin 1 beta; TNF-α: tumor necrosis factor alpha; M2: macrophages M2 phenotype; MDA: malondialdehyde. Reprinted from Refs. [101,120] with permission.

Fig. 6

Nanomedicine design based on lipid metabolism applied in cancer. (A) Schematic illustrating the preparation processes of the oleanolic acid@Fe-single-atom catalysts (SAC)@erythrocyte membrane (EM) nanoparticles and the anticancer mechanisms for chemodynamic therapy (CDT) [127]. (B) Schematic presentation on the fabrication processes of the molecularly self-engineered lipid peroxidation (LPO) nano-amplifier FIN56-AA-DSPE-SS-PEG_2K nanoparticles (FAS NPs) and the mechanisms for ferroptosis-driven tumor therapy [129]. ACSL4: acyl-CoA synthetase long-chain family member 4; PUFAs: polyunsaturated fatty acids; AA: arachidonic acid; DSPE-SS-PEG_2K: a small amount of disulfide bond-containing lipid-poly(ethylene glycol) (PEG); PL-OOH: phospholipid (PL) hydroperoxides; GSH: glutathione; ROS: reactive oxygen species; GPX4: GSH peroxidase 4; PL-OH: PL alcohols. Reprinted from Refs. [127,129] with permission.

Fig. 7

Schematic illustrating the application of Se/albumin nanoparticles (SA NPs) for inhibiting ferroptosis [132]. AKI: acute kidney injury. Reprinted from Ref. [132] with permission.

Fig. 8

Nanomedicine design based on iron metabolism applied in cancer. (A) Schematic illustration of the preparation processes of the mechano-responsive leapfrog micelles (protoporphyrin IX (PpIX)@M_Fc) and the mechanisms of collaborative sonodynamic therapy (SDT) and chemodynamic therapy (CDT) for apoptotic and ferroptotic cancer therapy [135]. (B) Fabrication procedures and antitumor mechanisms of ferritin (Fn)-targeting nanoparticles (chlorin e6 (Ce6)-poly(ethylene glycol) (PEG)-HKN₁₅ nanoparticles (NPs)) for synergistic photodynamic therapy (PDT) and ferroptosis therapy [137]. M_Fc: amphiphilic methoxyl PEG (mPEG)-polylysine (PLys)-ferrocene (Fc) micelles; US: ultrasound; GSH: glutathione; Trx: thioredoxin; k₁: first-order dissociation energy; k₂: second-order dissociation energy; ROS: lipid reactive oxygen species; GSSG: oxidized GSH. Reprinted from Refs. [135,137] with permission.

Fig. 9

Preparation of nanoswords (Fe-doped titanite) on implants for killing bacteria and improving osteogenesis [138]. (A) Schematic on the preparation processes of nanoswords. (B) Mechanism of killing bacteria and improving osteogenesis by nanosword. MAO: microarc oxidation; HT: hydrothermal treatment; ALP: alkaline phosphatase; Runx-2, OPN, OCN, Col-1, and BMP2: some typical genes for assessing the osteogenesis ability of osteoblasts; ADP: adenosine diphosphate; ATP: adenosine triphosphate; F1: F1 subunit of the ATP synthase complex; F0: F0 subunit of the ATP synthase complex; LPO: lipid peroxidation; GSH: glutathione; ROS: reactive oxygen species. Reprinted from Ref. [138] with permission.

Fig. 10

Nanomedicine design based on nicotinamide adenine dinucleotide (NADH)/ferroptosis suppressor protein 1 (FSP1)/coenzyme Q10 (CoQ10) mechanism applied in cancer and ischaemic stroke. (A) Schematic on the preparation processes and the antitumor mechanism of the metabolic intervention nanoparticles Cu-silk fibrin (SF) rosuvastatin (RSV) nanoparticles (Cu-SF(RSV) NPs) for triple-negative breast cancer (TNBC) [141]. (B) Schematic mechanism of the anti-inflammatory, antioxidative stress, and ferroptosis inhibition properties of nanoparticles deliver ginkgolide B (GB) with encapsulated platelet membrane (PM) (PM-GB) in ischaemic stroke and the preparation processes [142]. NAD(P)H: NADH phosphate; NAD(P)⁺: oxidized form of NADPH; CoQ: ubiquinone; CoQH2: ubiquinol; LPO: lipid peroxidation; MDA: malondialdehyde; SOD: superoxide dismutase; GSH-Px: glutathione (GSH) peroxidase; TNF-α: tumor necrosis factor alpha; IL: interleukin; NF-κB: nuclear factor-kappaB; GPX4: GSH peroxidase 4; NRF2: nuclear factor erythroid 2-related factor 2; HO-1: heme oxygenase-1; PTGS2: prostaglandin endoperoxide synthase 2. Reproduced from Refs. [141,142] with permission.

Fig. 11

Nanomedicine design based on dihydroorotate (DHO) dehydrogenase (DHODH) mediated ferroptosis defense mechanism applied in cancer. (A) Schematic illustration of the synthesis of magnetic nanoparticles (MNP)@brequinar (BQR)@angiopep-2 (ANG)-exosome (EXO)-small interfering RNA glutathione peroxidase 4 (siGPX4) (MNP@BQR@ANG-EXO-siGPX4) and the mechanisms underlying the induction of glioblastoma (GBM) cell ferroptosis [144]. (B) Schematic illustration of the construction and theranostic mechanism of the layered double hydroxide (LDH) nanoplatform co-loaded with ferroptosis agent iron oxide nanoparticles (IONs) and the DHODH inhibitor (siR/IONs@LDH) in nanomaterial-mediated tumor ferroptosis therapy [145]. TEOS: silicon tetraacetate; APTMS: (3-Aminopropyl) trimethoxysilane; hMSCs: human mesenchymal stromal cells; BBB: blood-brain barrier; LRP-1: lipoprotein receptor protein 1; GPX4^mito: GPX4 in mitochondrion; ROS: reactive oxygen species; GPX4^cyto: GPX4 in cytoplasm; siDHODH: DHODH inhibitor; siR@LDH: a siRNA@layered double hydroxide; MRI: magnetic resonance imaging; LPO: lipid peroxidation. Reprinted from Refs. [144,145] with permission.

Fig. 12

Yin Yang symbol of agonists or inhibitors activating or inhibiting ferroptosis to treat multiple diseases. NFS1: nitrogen-fixing protein 1; TFR1: transferrin receptor 1; Nrf2: nuclear factor erythroid 2-related factor 2; STEAP3: six-transmembrane epithelial antigen of prostate 3; HMOX1: heme oxygenase 1; DHODH: dihydroorotate (DHO) dehydrogenase; FTH1: ferritin (Fn) heavy chain 1; BQR: brequinar; GCH1: guanosine triphosphate (GTP) cyclohydrolase 1; DFOM: deferoxamine (DFO) mesylate; FSP1: ferroptosis suppressor protein 1; PDPT: palladium pyrithione complex; ACSL4: acyl-CoA synthetase long-chain family member 4; NCOA4: nuclear receptor coactivator 4; AD: Alzheimer's disease; AKI: acute kidney injury.