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@ARTICLE{Schubert:303645,
      author       = {A. Schubert and M. E. Lobo Barbosa da Silva and T. Ambrock
                      and O. Terosian and A. Malyshkina and C. Padberg and S.
                      Larafa and J. Matschke$^*$ and J. Fandrey and Y. Henning},
      title        = {{T}argeting hypoxia-inducible factor-1 in a hypoxidative
                      stress model protects retinal pigment epithelium cells from
                      cell death and metabolic dysregulation.},
      journal      = {Cell death discovery},
      volume       = {11},
      number       = {1},
      issn         = {2058-7716},
      address      = {London},
      publisher    = {Nature Publishing Group},
      reportid     = {DKFZ-2025-01709},
      pages        = {380},
      year         = {2025},
      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.},
      cin          = {ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40813365},
      pmc          = {pmc:PMC12354819},
      doi          = {10.1038/s41420-025-02675-7},
      url          = {https://inrepo02.dkfz.de/record/303645},
}