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Non-Erythropoietic EPO (EPO-R76E) Protects RPE Cells from Ferroptosis by Modulating the Labile Iron Pool and
Sundaramoorthy Gopi1, George T Prodanoff1, Christopher L Passaglia2
1Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USA.
Antioxidants (Basel, Switzerland)
|May 27, 2026
Summary
EPO-R76E protects retinal cells from iron overload and ferroptosis, a key factor in dry age-related macular degeneration. This variant reduces iron, boosts antioxidant defenses, and enhances cellular cleanup, offering a novel therapeutic approach.
Area of Science:
- Ophthalmology
- Cell Biology
- Neuroscience
Background:
- Dry age-related macular degeneration (AMD) involves retinal pigment epithelium (RPE) degeneration.
- Iron overload and ferroptosis create a toxic cycle contributing to RPE damage in dry AMD.
Purpose of the Study:
- To investigate the protective effects of EPO-R76E, a modified erythropoietin variant, against iron-induced RPE toxicity and ferroptosis.
- To elucidate the molecular mechanisms by which EPO-R76E preserves RPE health.
Main Methods:
- ARPE-19 cells were treated with ferric ammonium citrate (FAC) to induce iron toxicity.
- EPO-R76E treatment was applied to assess its protective effects and impact on cellular pathways.
- Intracellular labile iron levels, lipid peroxidation, Glutathione Peroxidase 4 (GPX4), NRF2 antioxidant axis, and autophagic flux were evaluated.
Main Results:
- EPO-R76E significantly protected ARPE-19 cells against ferroptosis induced by iron overload.
- The variant reduced intracellular labile iron and quenched lipid peroxidation.
- EPO-R76E upregulated GPX4, activated the NRF2 antioxidant pathway, and enhanced autophagic flux.
Conclusions:
- EPO-R76E effectively interrupts the iron overload-ferroptosis cycle in RPE cells.
- Its mechanisms involve iron sequestration, enhanced antioxidant signaling, and improved cellular clearance.
- EPO-R76E presents a promising gene-based therapeutic candidate for retinal degeneration by targeting fundamental injury mechanisms.
Keywords:
Epo-R76EGPX4LC3BNRF2 signalingage-related macular degeneration (AMD)antioxidantsautophagyferric ammonium citrate (FAC)ferroptosisgene therapyiron homeostasislabile iron poollipid peroxidationmodified variant of erythropoietinneuroprotectionoxidative stressp62/SQSTM1retinal pigment epithelium (RPE)
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