Table 1.
The mechanism of ferroptosis-related targets in ophthalmic diseases.
| Ophthalmic diseases | Ferroptosis-related targets | Study subject | Mechanism | Reference |
|---|---|---|---|---|
| Corneal injury | GPX4 | HCECs, C57BL/6 mice | Downregulation of GPX4 can promote the production of LDH and lipid peroxidation products such as 4-HNE | (148) |
| Lipid ROS | Male ICR mice | High levels of ROS can upregulate the expression of NOX2, NOX4, VEGF, and MMPs | (149) | |
| Lipid ROS | HCECs | Accumulation of ROS leads to the upregulation of ferroptosis promoters and the downregulation of ferroptosis inhibitors | (150) | |
| GPX4 | HCE-S cells | After exposure to Phenylarsine oxide, the expression of GPX4 in HCE-S cells is significantly reduced, indicating that Phenylarsine oxide induces ferroptosis mediated by lipid peroxidation in HCE-S cells | (151) | |
| GSH;GPX4 | Male SD rats | siVEGF-TIL can inhibit oxidative stress, inflammation, and the expression of VEGF in vitro, and effectively maintain corneal transparency in vivo, accelerate epithelialization, and inhibit corneal neovascularization | (152) | |
| Ferrous ion | HCE-T cells | Exposure to CSE induces lipid peroxidation and the accumulation of ferrous ions within the lysosomal compartments | (153) | |
| Cataracts | SIRT6 | Male SD rats | Melatonin inhibits ferroptosis through the SIRT6/p-Nrf2/GPX4 and SIRT6/COA4/FTH1 pathways | (154) |
| Nrf2, ferrous ion | Female C57BL/6J mice | Nrf2 may affect ferritin degradation by decreasing the expression of NCOA4 | (155) | |
| GSK-3β/Nrf2 | Female C57BL/6J mice | Targeting the balance of GSK-3β/Nrf2 can alleviate ferroptosis in LECs | (156) | |
| GPX4 | LECs | Inhibition of IncRNA MEG3 by interacting with PTBP1 promotes the decay of GPX4 messenger RNA, accelerating cellular vitality and inhibiting ferroptosis | (157) | |
| GPX4 | Male C57BL/6J mice, SD rats | Astaxanthin-mediated targeting of GPX4 may alleviate damage to human LECs by inhibiting ferroptosis and improving oxidative stress | (158) | |
| GPX4 | ARCC patients | GPX4 downregulation enhanced LEC ferroptosis and decreased viability via RSL3 in SRA01/04 cells | (159) | |
| Hippo pathway | LECs | Downregulation of KRAs might restrain ferroptosis and affect Hippo pathway in cataract | (160) | |
| System Xc-, GPX4 | LECs | System Xc inhibitor Erastin and GPX4 inhibitor RSL3 can induce ferroptosis in human LECs in vitro and in mouse corneal epithelium in vitro. | (161) | |
| Ferrous ion | LECs | The iron released from heme by HMOX1 may play a key role in increasing the sensitivity of human LECs to erastin | (162) | |
| GPX-1 | C57BL/6 mice | Lipid peroxides are substrates for GPX-1, and lenses with elevated levels of GPX-1 activity can resist the cytotoxic effects of H2O2 | (163) | |
| Glaucoma | MAPK;SLC7A11;GPX4 | Male SD rats | SB202190 can inhibit ferroptosis by regulating SLC7A11/GPX4 pathways, protecting retinal ganglion cells | (164) |
| GPX4;FSP1;Nrf2 | Male New Zealand rabbits | Overexpression of mitochondrial GPX4 rescued artesunate-induced lipid peroxidation and ferroptosis. FSP1 and Nrf2, which are also inhibited by artesunate. | (165) | |
| GSH, ROS | RGC-5 cells | GGT1 inhibits autophagy in RGC-5 cells by targeting GCLC, further suppressing the occurrence of cellular ferroptosis | (166) | |
| NCOA4-FTH1 | Male C57BL/6 mice | The NCOA4-FTH1-mediated iron metabolism disorder and ferroptosis play a role in glaucomatous RGCs | (167) | |
| GPX4;System Xc- | Male Wistar rats, Male C57BL/6J mice | Treatment with ONC leads to a significant downregulation of GPX4 and system Xc- in rat retinas, accompanied by increased levels of peroxidized lipids and iron. | (19) | |
| Serum ferritin | Korean patients | Higher serum ferritin levels are associated with an increased likelihood of glaucoma | (168, 169) | |
| AMD | Lipid ROS | ARPE-19;hRPE cells | Necrostatin-1 can inhibit the activation of RIPK1/RIPK3 and the accumulation of lipid ROS | (170) |
| Ferrous ion | C57BL6 mice;ARPE-19 cells | Knocking down ZIP8 can significantly inhibit the ferroptosis induced by sodium iodate-induced oxidative stress in RPE cells | (171) | |
| Nrf2 | 661W cells;C57BL/6 mice | Melatonin inhibits the GSK-3β/Fyn-dependent nuclear translocation of Nrf2 | (172) | |
| GPX4;FTH1 | C57BL/6 mice | Overexpression of PEDF can upregulate the expression of GPX4 and FTH1 | (173) | |
| Lipid ROS | ARPE-19;hTERT RPE-1 cells | Increasing the intracellular concentration of POS or DHA can enhance the susceptibility of the RPE to oxidative stress damage | (174) | |
| Ferrous ion, Hydroxyl radicals | ARPE-19 | HIF exacerbates oxidative stress-induced ferroptosis in RPE cells | (175) | |
| Mitochondrial ROS | ARPE-19, C57BL/6J mice | CircSPECC1, mediated by m6A modification and sponging miR-145-5p, resists oxidative stress injuries and maintains lipid metabolism in RPE | (176) | |
| KEAP1, NRF2, Ferrous ion | C57BL/6J mice | Overexpression of HO-1 leads to a significant increase in Fe2+ levels in photoreceptor cells, promoting the excessive production of ROS | (177) | |
| Lipid peroxidation | ARPE-19, OMM-1 | Ommochrome extract seem to be promising regarding protection against lipid peroxidation in healthy ocular cells | (178) | |
| Ferrous ion | C57BL/6J mice | Chac1 plays a key role in ferroptosis induced by oxidative stress by regulating GSH depletion. | (179) | |
| Nrf2 | ARPE-19 | GBE pre-treatment attenuates pro-oxidant stress and protects human RPE cells from oxidative injury by modulating ERK1/2-Nrf2 axis | (180) | |
| FTH1, GPX | C57BL/6J mice | Deregulated LCN2-iron axis triggers oxidative damage and lipid peroxidation in RPE cells | (181) | |
| Lipid ROS | C57BL/6J mice | CaPB effectively prevented the degeneration of RPE, significantly rescuing retinal structure and visual function | (182) | |
| Nrf2, SLC7A11, Ferrous ion | Male C57BL/6 mice, ARPE-19 cells | Nrf2-SLC7A11-HO-1 leads to RPE cell death and subsequent photoreceptor degeneration through the accumulation of ferrous iron ions and fatal oxidative stress | (183) | |
| GPX4, FSP1 | HRPEpiC, ARPE-19 cells, Male C57BL/6J mice | Ferrostatin-1 significantly ameliorated the compromised GSH-GPX4 and FSP1-CoQ10-NADH signaling | (81) | |
| L-Ft | Male C57BL/6J mice | IVT FAC induced iron accumulation in Müller glia and myeloid cells, and the formation of lipidperoxidation products | (184) | |
| SLC40A1, System Xc-, Ferrous ion, GPX4 | ARPE-19 cells | IFN-γ raises Fe2+ by inhibiting the iron exporter SLC40A1 and induces GSH depletion by blocking the System Xc- transporter. | (185) | |
| GSH | ARPE-19 cells | GSH depletion induces ferroptosis | (186) | |
| ferrous ion, ACSL4, System Xc- | C57BL/6J mice | Iron overload, GSH depletion, and mitochondrial damage cause the production of ROS, which, together with the activation of ACSL4, promote lipid peroxidation and thus induce ferroptosis. | (187) | |
| SLC7A11, Ferrous ion, Nrf2, GPX4 | ARPE-19 cells, C57BL/6J mice | SLC7A11 overexpression induced resistance to erastin or RSL3-induced ferroptosis | (188) | |
| Ferrous ion, SLC7A11, GPX4 | 661W cells;Male SD rats | Light exposure significantly induced changes, including iron accumulation, mitochondrial shrinkage, GSH depletion, increased MDA, and decreased SLC7A11 and GPX4. | (189) | |
| DR | GPX4, FTH1, ACSL4, TFRC | HRMECs | Under high glucose conditions, ferroptosis is associated with increased levels of ROS, lipid peroxidation, and iron content | (190) |
| HMOX1 | C57BL/6J mice | HMOX1 expression correlated with M2 macrophage infiltration and ferroptosis | (191) | |
| ROS | SD rats | Inhibition of AQP4 inhibits the ferroptosis and oxidative stress in Muller cells by downregulating TRPV4 | (130) | |
| Ferrous ion, ROS | ARPE-19 cells | USP48 overexpression deubiquitinated SLC1A5 to elevate cell proliferation and suppress ferroptosis and oxidative stress | (192) | |
| ACSL4, TFR1, SLC7A11, GPX4, Ferrous ion | hRMECs | Overexpression of PIM1 inhibited the inflammatory response, oxidative stress, cell migration, and tube formation potential in hRMECs, whereas elevated tight junction protein levels. | (193) | |
| GPX4-YAP | DR patients, Male C57BL/6 mice, hRCECs | Pipecolic acid may impede the progression of DR by inhibiting the YAP-GPX4 signaling pathway | (194) | |
| GPX4, SLC7A11, ACSL4, FTH1, NCOA4 | 661W cells, Male C57BL/6J mice | The expression of GPX4 and SLC7A11 was downregulated, while the expression of ACSL4, FTH1, and NCOA4 was upregulated in the 661W cells cultured under HG conditions and in the photoreceptor cells in diabetic mice. | (195) | |
| SLC7A11, GPX4 | hRMECs | Ferroptosis-related genes are significantly enriched in processes of ROS metabolism, iron ion reactions | (196) | |
| GPX4, FTH1, Ferrous ion | ARPE-19 cells, C57BL/6J mice | Sestrin2 inhibits ferroptosis by inhibiting STAT3 phosphorylation and ER stress | (197, 198) | |
| Nrf2, GPX4 | ARPE-19 cells | Maresin-1 inhibits high glucose induced ferroptosis in ARPE-19 cells by activating the Nrf2/HO-1/GPX4 pathway | (199) | |
| GPX4, FSP-1 | Male C57BL/6 mice, ARPE-19 cells | 1,8-Cineole ameliorates DR by inhibiting RPE ferroptosis via PPAR-γ/TXNIP pathways | (200) | |
| Ferritin | ARPE-19 cells | BECN1, HERC2, ATG7, and BCAT2 might regulate ferritinophagy to influence its development and progression | (201) | |
| NRF2, GPX4, Ferrous ion | HRECs | Amygdalin treatment inhibited ferroptosis and oxidative stress in HG-stimulated HRECs by activating the NRF2/ARE signaling pathway | (202) | |
| GPX4 | ARPE-19 cells | Ferrostatin-1 alleviates tissue and cell damage in DR by improving the antioxidant capacity of the Xc--GPX4 system | (203) | |
| FTH1 | Tg (hb9: GFP) zebrafish | ACR could directly activate ferroptosis and impairs peripheral neurogenesis | (204) | |
| GPX4, SLC7A11, Ferrous ion | hRMVECs | 25-hydroxyvitamin D3 inhibits oxidative stress and ferroptosis in retinal microvascular endothelial cells induced by high glucose through down-regulation of miR-93 | (205) | |
| GPX4, GSH, Ferrous ion | DR patients | Compared with the normal group, GPX4 and GSH concentrations were significantly lower, and LPO, Fe2+, and ROS concentrations were significantly higher in DR patients | (206) | |
| ACSL4 | Male SD rats | Glia maturation factor-β induces ferroptosis by impairing chaperone-mediated autophagic degradation of ACSL4 in early DR | (207) | |
| SLC7A11, GPX4 | Male C57BL/6 mice, ARPE-19 cells | Downregulation of FABP4 alleviates lipid peroxidation and oxidative stress in DR by regulating peroxisome proliferator-activated receptor y-mediated ferroptosis | (208) | |
| Nrf2, GPX4 | ARPE-19 cells | Astragaloside-IV alleviates high glucose-induced ferroptosis in RPE cells by disrupting the expression of miR-138-5p/Sirt1/ Nrf2 | (209) | |
| GSH, Ferrous ion | ARPE-19 cells | Downregulation of Circular RNA PSEN1 ameliorates ferroptosis of the high glucose treated RPE cells via miR-200b-3p/cofilin-2 axis | (210) | |
| GPX4 | HRCECs | TRIM46 aggravated high glucose-induced hyper permeability and inflammatory response in human retinal capillary endothelial cells by promoting IκBα ubiquitination | (211, 212) | |
| SLC1A5 | ARPE-19 cells | miR-338-3p targeted the 3' untranslated regions (3'UTR) of SLC1A5 for its inhibition and degradation, and high glucose downregulated SLC1A5 by upregulating miR-338-3p in RPE cells. | (213) | |
| RP | SLC7A11, GPX4, P53 | 661 W cells | Fructus Lycii and Salvia miltiorrhiza Bunge extract attenuate oxidative stress-induced photoreceptor ferroptosis | (50) |
| ROS | ARPE-19 cells | TXNIP-Trx-TrxR redox pathway may participate in RPE dysfunction | (214) | |
| NRF2, GPX4, SLC7A11 | rd10 mice, C57BL/6J mice | Qi-Shen-Tang alleviates retinitis pigmentosa by inhibiting ferroptotic features via the NRF2/GPX4 signaling pathway | (33) | |
| Ferritin, Ferrous ion | rd10 mice | RP are associated with altered iron homeostasis regardless of the primary insult | (215) | |
| RB | GPX4, SLC7A11 | A375, SK-Mel-28, and FO-1 cells | Hyperforin Enhances HO-1 Expression Triggering Lipid Peroxidation in BRAF-Mutated Melanoma Cells and Hampers the Expression of Pro-Metastatic Markers | (216) |
| GPX4, FTH1, ACSL4 | Y79 cells, Y79/DDP cells | USP14 might suppress the DDP resistance in RB by mediating ferroptosis | (217) | |
| Hippo pathway | Y79 cells, SO-RB50 cells, RB3823 cells | Expression of YAP suppresses cell proliferation and elevates the sensitivity of chemotherapy in RB cells through lipid-peroxidation induced ferroptosis | (218) | |
| GPX4, FTH1, SLC7A11, P62 | ARPE-19, Y79 cells, Male BALB/c nude mice | Nuclear translocation of CTSB induces lysosomal stress, which eventually leads to ferroptosis | (219) | |
| FTH1, NCOA4 | Y79 cells, WERI-Rb-1 cells | The anticancer potential of an itaconate derivative in RB cell relies on ferritinophagy-mediated ferroptosis | (220) | |
| P53 | TKO cells | Deletion of RB genes enhanced ferroptosis | (221) | |
| RD | Transferrin, Ferrous ion | RD patients, Male Long-Evans rats | TF decreases both apoptosis and necroptosis induced by RD | (222) |
ACSL4, Acyl-CoA synthetase long-chain family member 4; AMD, Age-related macular degeneration; ARCCs, Age-related cortical cataracts; Chac1, GSH-specific γ-glutamylcyclotransferase 1; CSE, Cigarette smoke extract; DHA, Docosahexaenoic acid; DR, Diabetic retinopathy; FABP4, Fatty acid binding protein 4; FTH1, Ferritin heavy chain-1; GBE, Ginkgo biloba extracts; GCLC, Glutamate cysteine ligase catalytic subunit; GGT1, Gamma-glutamyl transpeptidase 1; GPX4, Glutathione peroxidase 4; HCECs, Human corneal epithelial cells; HCE-S, Human corneal epithelial cells; HIF, Hypoxia-inducible factor; HMOX1, Heme oxygenase 1; HRCECs, Human retinal capillary endothelial cells; IFN-γ, Interferon-gamma; KEAP1, Kelch-like ECH-associated protein 1; LECs, Lens epithelial cells; L-Ft, Ferritin light chain; MDA, Malondialdehyde; MMPs, Matrix metalloproteinases; Nrf2, Nuclear factor erythroid 2-related factor 2; ONC, Optic nerve crush; PEDF, Pigment epithelium-derived factor; POS, Photoreceptor outer segments; RB, Retinoblastoma; RD, Retinal detachment; RGC-5, Retinal ganglion cells; RGCs, Retinal ganglion cells; ROS, Reactive oxygen species; RP, Retinitis pigmentosa; RPE, Retinal pigment epithelium; SD, Sprague–Dawley; VEGF, Vascular endothelial growth factor.