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| Home > Publications database > Targeting hypoxia-inducible factor-1 in a hypoxidative stress model protects retinal pigment epithelium cells from cell death and metabolic dysregulation. > print |
| 001 | 303645 | ||
| 005 | 20250824022531.0 | ||
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| 100 | 1 | _ | |a Schubert, Annika |0 0009-0002-4777-5922 |b 0 |
| 245 | _ | _ | |a Targeting hypoxia-inducible factor-1 in a hypoxidative stress model protects retinal pigment epithelium cells from cell death and metabolic dysregulation. |
| 260 | _ | _ | |a London |c 2025 |b Nature Publishing Group |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 520 | _ | _ | |a Oxidative stress and hypoxia lead to dysfunction of retinal pigment epithelium (RPE) cells and are hallmarks of diseases such as age-related macular degeneration (AMD), the most common blinding disease in the elderly population. We have previously shown that a combination of these two risk factors, i.e. hypoxidative stress, exacerbates RPE cell death by ferroptosis. Hypoxia leads to stabilization of hypoxia-inducible factors (HIFs), key regulators of cellular adaptation to hypoxic conditions. In the present study, we have therefore investigated the roles of HIF-1 and HIF-2 in RPE cell death in a human RPE cell line under hypoxidative stress. For this purpose, we conducted siRNA-mediated knockdowns of the α-subunits of HIF-1 and HIF-2. We found that especially iron metabolism, in particular the expression of transferrin receptor 1 (TFR1) was affected by HIF-1α silencing, resulting in decreased intracellular iron levels and ferroptosis susceptibility. We also found that heme oxygenase 1 (HO-1) contributed to cell death by hypoxidative stress. In addition, we also observed that cell metabolism was improved by HIF-1α silencing under hypoxia, most likely contributing to the protective effect. Furthermore, we identified an FDA-approved small molecule inhibitor, Vorinostat, to downregulate HIF-1α, TFR1, and HO-1 and improve cell metabolism, which eventually resulted in a full rescue of RPE cells from hypoxidative stress-induced cell death. In conclusion, this study highlights the importance of considering targeted HIF inhibition as a promising approach to protect RPE cells from degeneration. |
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| 700 | 1 | _ | |a Lobo Barbosa da Silva, Maria Eduarda |b 1 |
| 700 | 1 | _ | |a Ambrock, Tabea |b 2 |
| 700 | 1 | _ | |a Terosian, Orbel |0 0009-0003-9280-6393 |b 3 |
| 700 | 1 | _ | |a Malyshkina, Anna |0 0000-0001-5199-5472 |b 4 |
| 700 | 1 | _ | |a Padberg, Claudia |b 5 |
| 700 | 1 | _ | |a Larafa, Safa |0 0000-0001-5245-2373 |b 6 |
| 700 | 1 | _ | |a Matschke, Johann |0 0000-0003-4878-8741 |b 7 |
| 700 | 1 | _ | |a Fandrey, Joachim |b 8 |
| 700 | 1 | _ | |a Henning, Yoshiyuki |0 0000-0002-0166-2204 |b 9 |
| 773 | _ | _ | |a 10.1038/s41420-025-02675-7 |g Vol. 11, no. 1, p. 380 |0 PERI:(DE-600)2842546-7 |n 1 |p 380 |t Cell death discovery |v 11 |y 2025 |x 2058-7716 |
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