Targeting hypoxia-inducible factor-1 in a hypoxidative stress model protects retinal pigment epithelium cells from cell death and metabolic dysregulation
Abstract 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...
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Nature Publishing Group
2025-08-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02675-7 |
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| author | Annika Schubert Maria Eduarda Lobo Barbosa da Silva Tabea Ambrock Orbel Terosian Anna Malyshkina Claudia Padberg Safa Larafa Johann Matschke Joachim Fandrey Yoshiyuki Henning |
| author_facet | Annika Schubert Maria Eduarda Lobo Barbosa da Silva Tabea Ambrock Orbel Terosian Anna Malyshkina Claudia Padberg Safa Larafa Johann Matschke Joachim Fandrey Yoshiyuki Henning |
| author_sort | Annika Schubert |
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| description | Abstract 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. |
| format | Article |
| id | doaj-art-df4d4e77559d43fc8b9d12d9062656f7 |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death Discovery |
| spelling | doaj-art-df4d4e77559d43fc8b9d12d9062656f72025-08-20T03:42:47ZengNature Publishing GroupCell Death Discovery2058-77162025-08-0111111210.1038/s41420-025-02675-7Targeting hypoxia-inducible factor-1 in a hypoxidative stress model protects retinal pigment epithelium cells from cell death and metabolic dysregulationAnnika Schubert0Maria Eduarda Lobo Barbosa da Silva1Tabea Ambrock2Orbel Terosian3Anna Malyshkina4Claudia Padberg5Safa Larafa6Johann Matschke7Joachim Fandrey8Yoshiyuki Henning9Institute of Physiology, University Hospital Essen, University of Duisburg-EssenInstitute of Physiology, University Hospital Essen, University of Duisburg-EssenInstitute of Physiology, University Hospital Essen, University of Duisburg-EssenInstitute of Physiology, University Hospital Essen, University of Duisburg-EssenInstitute of Physiology, University Hospital Essen, University of Duisburg-EssenInstitute of Physiology, University Hospital Essen, University of Duisburg-EssenInstitute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-EssenInstitute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-EssenInstitute of Physiology, University Hospital Essen, University of Duisburg-EssenInstitute of Physiology, University Hospital Essen, University of Duisburg-EssenAbstract 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.https://doi.org/10.1038/s41420-025-02675-7 |
| spellingShingle | Annika Schubert Maria Eduarda Lobo Barbosa da Silva Tabea Ambrock Orbel Terosian Anna Malyshkina Claudia Padberg Safa Larafa Johann Matschke Joachim Fandrey Yoshiyuki Henning Targeting hypoxia-inducible factor-1 in a hypoxidative stress model protects retinal pigment epithelium cells from cell death and metabolic dysregulation Cell Death Discovery |
| title | Targeting hypoxia-inducible factor-1 in a hypoxidative stress model protects retinal pigment epithelium cells from cell death and metabolic dysregulation |
| title_full | Targeting hypoxia-inducible factor-1 in a hypoxidative stress model protects retinal pigment epithelium cells from cell death and metabolic dysregulation |
| title_fullStr | Targeting hypoxia-inducible factor-1 in a hypoxidative stress model protects retinal pigment epithelium cells from cell death and metabolic dysregulation |
| title_full_unstemmed | Targeting hypoxia-inducible factor-1 in a hypoxidative stress model protects retinal pigment epithelium cells from cell death and metabolic dysregulation |
| title_short | Targeting hypoxia-inducible factor-1 in a hypoxidative stress model protects retinal pigment epithelium cells from cell death and metabolic dysregulation |
| title_sort | targeting hypoxia inducible factor 1 in a hypoxidative stress model protects retinal pigment epithelium cells from cell death and metabolic dysregulation |
| url | https://doi.org/10.1038/s41420-025-02675-7 |
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