Ferroptosis-centered Disease Response Information

General Information of the Disease (ID: DIS00087)
Name
Retinopathy
ICD
ICD-11: 9B71
Full List of Target(s) of This Ferroptosis-centered Disease
Nuclear factor erythroid 2-related factor 2 (NFE2L2)
 Target Info 
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Diabetic retinopathy [ICD-11: 9B71.0]
Responsed Drug Astragaloside IV Investigative
 Drug Info 
Responsed Regulator hsa-miR-138-5p (miRNA) Driver
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model ARPE-19 cells Normal Homo sapiens CVCL_0145
Response regulation Astragaloside IV (AS-IV) inhibited miR-138-5p expression, subsequently increasing Sirt1/Nrf2 activity and cellular antioxidant capacity to alleviate ferroptosis, resulting decreased cell death, which potentially inhibits the diabetic retinopathy pathological process.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Diabetic retinopathy [ICD-11: 9B71.0]
Responsed Drug Astragaloside IV Investigative
 Drug Info 
Responsed Regulator NAD-dependent protein deacetylase sirtuin-1 (SIRT1) Suppressor
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model ARPE-19 cells Normal Homo sapiens CVCL_0145
Response regulation Astragaloside IV (AS-IV) inhibited miR-138-5p expression, subsequently increasing Sirt1/Nrf2 activity and cellular antioxidant capacity to alleviate ferroptosis, resulting decreased cell death, which potentially inhibits the diabetic retinopathy pathological process.
Transferrin receptor protein 1 (TFRC)
 Target Info 
In total 3 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Marker/Suppressor/Driver
Responsed Disease Diabetic retinopathy [ICD-11: 9B71.0]
Responsed Regulator Circ-PSEN1 (circRNA) Driver
 Regulator Info 
Pathway Response Glutathione metabolism hsa00480
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model ARPE-19 cells Normal Homo sapiens CVCL_0145
Response regulation Downregulation of circ-PSEN1 ameliorates HG-induced ferroptosis in ARPE19 cells via miR-200b-3p/CFL2 and may be a novel therapeutic target for diabetic retinopathy. Enhancement of CFL2 suppressed the mRNA and protein expression of GPX4 and SLC7A11. However, TFR1 expression was promoted.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Marker/Suppressor/Driver
Responsed Disease Diabetic retinopathy [ICD-11: 9B71.0]
Responsed Regulator hsa-miR-200b-3p (miRNA) Suppressor
 Regulator Info 
Pathway Response Glutathione metabolism hsa00480
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model ARPE-19 cells Normal Homo sapiens CVCL_0145
Response regulation Downregulation of circ-PSEN1 ameliorates HG-induced ferroptosis in ARPE19 cells via miR-200b-3p/CFL2 and may be a novel therapeutic target for diabetic retinopathy. Enhancement of CFL2 suppressed the mRNA and protein expression of GPX4 and SLC7A11. However, TFR1 expression was promoted.
Experiment 3 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Marker/Suppressor/Driver
Responsed Disease Diabetic retinopathy [ICD-11: 9B71.0]
Responsed Regulator Cofilin-2 (CFL2) Driver
 Regulator Info 
Pathway Response Glutathione metabolism hsa00480
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model ARPE-19 cells Normal Homo sapiens CVCL_0145
Response regulation Downregulation of circ-PSEN1 ameliorates HG-induced ferroptosis in ARPE19 cells via miR-200b-3p/ CFL2 and may be a novel therapeutic target for diabetic retinopathy. Enhancement of CFL2 suppressed the mRNA and protein expression of GPX4 and SLC7A11. However, TFR1 expression was promoted.
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
 Target Info 
In total 4 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [3]
Target for Ferroptosis Suppressor
Responsed Disease Diabetic retinopathy [ICD-11: 9B71.0]
Responsed Regulator Tripartite motif-containing protein 46 (TRIM46) Driver
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HRCECs (Human retinal capillary endothelial cells)
Response regulation TRIM46 interacted with GPX4, an important enzyme that suppresses ferroptosis, and promoted GPX4 ubiquitination. The role of TRIM46 in GPX4 ubiquitination should inspire the future development of new therapies against diabetic retinopathy (DR).
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Suppressor
Responsed Disease Diabetic retinopathy [ICD-11: 9B71.0]
Responsed Regulator Circ-PSEN1 (circRNA) Driver
 Regulator Info 
Pathway Response Glutathione metabolism hsa00480
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model ARPE-19 cells Normal Homo sapiens CVCL_0145
Response regulation Downregulation of circ-PSEN1 ameliorates HG-induced ferroptosis in ARPE19 cells via miR-200b-3p/CFL2 and may be a novel therapeutic target for diabetic retinopathy. Enhancement of CFL2 suppressed the mRNA and protein expression of GPX4 and SLC7A11. However, TFR1 expression was promoted.
Experiment 3 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Suppressor
Responsed Disease Diabetic retinopathy [ICD-11: 9B71.0]
Responsed Regulator hsa-miR-200b-3p (miRNA) Suppressor
 Regulator Info 
Pathway Response Glutathione metabolism hsa00480
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model ARPE-19 cells Normal Homo sapiens CVCL_0145
Response regulation Downregulation of circ-PSEN1 ameliorates HG-induced ferroptosis in ARPE19 cells via miR-200b-3p/CFL2 and may be a novel therapeutic target for diabetic retinopathy. Enhancement of CFL2 suppressed the mRNA and protein expression of GPX4 and SLC7A11. However, TFR1 expression was promoted.
Experiment 4 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Suppressor
Responsed Disease Diabetic retinopathy [ICD-11: 9B71.0]
Responsed Regulator Cofilin-2 (CFL2) Driver
 Regulator Info 
Pathway Response Glutathione metabolism hsa00480
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model ARPE-19 cells Normal Homo sapiens CVCL_0145
Response regulation Downregulation of circ-PSEN1 ameliorates HG-induced ferroptosis in ARPE19 cells via miR-200b-3p/ CFL2 and may be a novel therapeutic target for diabetic retinopathy. Enhancement of CFL2 suppressed the mRNA and protein expression of GPX4 and SLC7A11. However, TFR1 expression was promoted.
Neutral amino acid transporter B(0) (SLC1A5)
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [4]
Target for Ferroptosis Driver
Responsed Disease Diabetic retinopathy [ICD-11: 9B71.0]
Responsed Regulator hsa-miR-338-3p (miRNA) Suppressor
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model ARPE-19 cells Normal Homo sapiens CVCL_0145
Response regulation High glucose upregulated miR-338-3p to cause SLC1A5-deficiency in RPE cells, resulting in oxidative stress mediated cell ferroptosis, which further caused RPE cell death and aggravate diabetic retinopathy (DR) progression.
Long-chain-fatty-acid--CoA ligase 4 (ACSL4)
 Target Info 
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [5]
Target for Ferroptosis Driver
Responsed Disease Diabetic retinopathy [ICD-11: 9B71.0]
Responsed Regulator hsa-miR-7-5p (miRNA) Suppressor
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model hRECs (Human retinal endothelial cells)
In Vivo Model
For in vivo experiments, the eyes in each group (n = 6) were enucleated carefully and processed for indirect immunofluorescence in whole-mount or cross-section as previously described. For cryosections, the eyes (n = 3 retinae from 3 mice) were fixed in 4% PFA at room temperature for 15 min. The frozen samples were then sliced transversely (6 um) at -20. For retinal flat-mounts, the eyes (n = 3 eyes from 3 mice) were fixed in 4% PFA at room temperature for 15 min, and the retinae were dissected out as cups. Both cryosections and retinal cups were blocked with PBS containing 0.5% Triton-X100 and 5% BSA at 4 overnight and included with the anti-CD31 and anti-GPX4 (1:100, ab125066, Abcam) primary antibodies.

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Response regulation ZFAS1 may act as a competing endogenous RNA by competitively binding with microRNA-7-5p (miR-7-5p) and modulating the expression of its downstream molecule acyl-CoA synthetase long-chain family member 4 (ACSL4), which is now identified as a classic driver gene of ferroptosis process. In conclusion, our results demonstrate that HG-induced ZFAS1 elevation activates ferroptosis in hRECs and the ZFAS1/ miR-7-5p/ACSL4 axis may serve as a therapeutic target for endothelial dysfunction in diabetic retinopathy.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [5]
Target for Ferroptosis Driver
Responsed Disease Diabetic retinopathy [ICD-11: 9B71.0]
Responsed Regulator ZFAS1 (IncRNA) Driver
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model hRECs (Human retinal endothelial cells)
In Vivo Model
For in vivo experiments, the eyes in each group (n = 6) were enucleated carefully and processed for indirect immunofluorescence in whole-mount or cross-section as previously described. For cryosections, the eyes (n = 3 retinae from 3 mice) were fixed in 4% PFA at room temperature for 15 min. The frozen samples were then sliced transversely (6 um) at -20. For retinal flat-mounts, the eyes (n = 3 eyes from 3 mice) were fixed in 4% PFA at room temperature for 15 min, and the retinae were dissected out as cups. Both cryosections and retinal cups were blocked with PBS containing 0.5% Triton-X100 and 5% BSA at 4 overnight and included with the anti-CD31 and anti-GPX4 (1:100, ab125066, Abcam) primary antibodies.

    Click to Show/Hide
Response regulation ZFAS1 may act as a competing endogenous RNA by competitively binding with microRNA-7-5p (miR-7-5p) and modulating the expression of its downstream molecule acyl-CoA synthetase long-chain family member 4 (ACSL4), which is now identified as a classic driver gene of ferroptosis process. In conclusion, our results demonstrate that HG-induced ZFAS1 elevation activates ferroptosis in hRECs and the ZFAS1/miR-7-5p/ACSL4 axis may serve as a therapeutic target for endothelial dysfunction in diabetic retinopathy.
Unspecific Target
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [6]
Responsed Disease Diabetic retinopathy [ICD-11: 9B71.0]
Responsed Regulator Tripartite motif-containing protein 46 (TRIM46) Driver
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
NF-kappa B signaling pathway hsa04064
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HRCECs (Human retinal capillary endothelial cells)
Response regulation Diabetic retinopathy (DR) as a severe diabetic complication contributes to blindness. TRIM46 interacts with IB to activate the NF-B signaling pathway, thereby enhancing cell proliferation inhibition, hyper permeability and the inflammatory response of HRCECs in a HG state.
References
Ref 1 Astragaloside-IV alleviates high glucose-induced ferroptosis in retinal pigment epithelial cells by disrupting the expression of miR-138-5p/Sirt1/Nrf2. Bioengineered. 2022 Apr;13(4):8240-8254. doi: 10.1080/21655979.2022.2049471.
Ref 2 Downregulation of Circular RNA PSEN1 ameliorates ferroptosis of the high glucose treated retinal pigment epithelial cells via miR-200b-3p/cofilin-2 axis. Bioengineered. 2021 Dec;12(2):12555-12567. doi: 10.1080/21655979.2021.2010369.
Ref 3 TRIM46 contributes to high glucose-induced ferroptosis and cell growth inhibition in human retinal capillary endothelial cells by facilitating GPX4 ubiquitination. Exp Cell Res. 2021 Oct 15;407(2):112800. doi: 10.1016/j.yexcr.2021.112800. Epub 2021 Sep 4.
Ref 4 A novel miR-338-3p/SLC1A5 axis reprograms retinal pigment epithelium to increases its resistance to high glucose-induced cell ferroptosis. J Mol Histol. 2022 Jun;53(3):561-571. doi: 10.1007/s10735-022-10070-0. Epub 2022 Mar 23.
Ref 5 lncRNA ZFAS1 Positively Facilitates Endothelial Ferroptosis via miR-7-5p/ACSL4 Axis in Diabetic Retinopathy. Oxid Med Cell Longev. 2022 Aug 31;2022:9004738. doi: 10.1155/2022/9004738. eCollection 2022.
Ref 6 TRIM46 aggravated high glucose-induced hyper permeability and inflammatory response in human retinal capillary endothelial cells by promoting IB ubiquitination. Eye Vis (Lond). 2022 Sep 5;9(1):35. doi: 10.1186/s40662-022-00305-2.