biostudies-literatureHenning YBundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)662https://www.ebi.ac.uk/biostudies/studies/S-EPMC9338085biostudies-literatureUnknown13(7)Oxidative stress and hypoxia in the retinal pigment epithelium (RPE) have long been considered major risk factors in the pathophysiology of age-related macular degeneration (AMD), but systematic investigation of the interplay between these two risk factors was lacking. For this purpose, we treated a human RPE cell line (ARPE-19) with sodium iodate (SI), an oxidative stress agent, together with dimethyloxalylglycine (DMOG) which leads to stabilization of hypoxia-inducible factors (HIFs), key regulators of cellular adaptation to hypoxic conditions. We found that HIF stabilization aggravated oxidative stress-induced cell death by SI and iron-dependent ferroptosis was identified as the main cell death mechanism. Ferroptotic cell death depends on the Fenton reaction where H₂O<sub>2</Cell death & diseaseHypoxia aggravates ferroptosis in RPE cells by promoting the Fenton reaction.PMC933808502NUK061B860245Larafa SMatschke JHenning YBlind USFandrey JfalseHypoxia aggravates ferroptosis in RPE cells by promoting the Fenton reaction.Oxidative stress and hypoxia in the retinal pigment epithelium (RPE) have long been considered major risk factors in the pathophysiology of age-related macular degeneration (AMD), but systematic investigation of the interplay between these two risk factors was lacking. For this purpose, we treated a human RPE cell line (ARPE-19) with sodium iodate (SI), an oxidative stress agent, together with dimethyloxalylglycine (DMOG) which leads to stabilization of hypoxia-inducible factors (HIFs), key regulators of cellular adaptation to hypoxic conditions. We found that HIF stabilization aggravated oxidative stress-induced cell death by SI and iron-dependent ferroptosis was identified as the main cell death mechanism. Ferroptotic cell death depends on the Fenton reaction where H₂O<sub>2</2022-01-01T00:00:00Z2022 Jul2025-04-27T03:25:01.638Z2025-04-06T18:47:08.238ZS-EPMC93380853590621110.1038/s41419-022-05121-z