# The role of ferroptosis in red cell aging in vivo and in vitro

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $724,266

## Abstract

PROJECT SUMMARY
Red blood cells (RBCs) are a perfect model to study oxidant stress. RBCs are the most abundant cell in
the body (84% of total human cells) and play an essential role in oxygen transport and thus in the regulation of
all oxygen-dependent metabolic processes. To facilitate this task, RBCs are loaded with hemoglobin (Hb) and
iron. Indeed, 66% of total bodily iron is in RBCs. As a result, the mature RBC faces significant oxidant stress
deriving from iron-dependent Fenton and Haber-Weiss redox chemistry. The lack of nuclei and organelles
prevents RBCs from synthesizing new proteins to replace oxidatively damaged components during the average
lifespan of 120 days in circulation. Every day over 200 billion RBCs are removed from the bloodstream and de
novo generated via erythropoiesis, a process that relies on the uptake of circulating iron in the ferric (oxidized)
state, and its reduction to the ferrous state. This process is catalyzed by the ferrireductase STEAP3 – a
transcriptionally-regulated target of tumor protein p53. Both p53 and STEAP3 are critical to erythropoiesis and
polymorphic in humans, whereby mutations in p53 - occurring in >50% of all cancers, 0.2% of all healthy humans
- are not just inherited, but commonly accumulate during organismal aging or exposure to carcinogens.
In genetic studies on murine models of in vitro aging of RBCs (i.e., under conditions that mimic blood storage
in the blood bank) we have documented that hypermorphic STEAP3 is associated with poor blood storage
quality, owing to increased oxidant stress and elevated lipid peroxidation. Iron-mediated non-apoptotic cell death
via lipid peroxidation is a hallmark of ferroptosis, a novel process of cell death investigated extensively in
nucleated cells, but hitherto ignored in iron-loaded RBCs. More than other cells, RBCs rely on antioxidant
systems to keep oxidant stress in check. A key antioxidant system is represented by the soluble tripeptide
glutathione, glutathione-dependent detoxification systems (e.g., glutathione-peroxidase 4 - GPX4 to counteract
lipid peroxidation) and oxidized glutathione recycling via NADPH-dependent enzymes. The main pathway that
sustains NADPH synthesis in RBCs is the pentose phosphate pathway. Glucose 6-phoshate dehydrogenase
(G6PD) is the rate-limiting enzyme of this pathway, an X-linked gene that is mutated in ~500 million people.
Oxidant damage to protein triggers formation of isoaspartyl damage, a process counteracted by the enzyme
PIMT. Relevant to this proposal, in other cell types p53 promotes ferroptosis by up-regulation of STEAP3 and
down-regulation of G6PD, while being itself negatively regulated by PIMT. Even though genetic and
pharmacological tools are available to regulate ferroptosis, these approaches are untested in mature RBCs,
which is the focus of this project. Relevance to public health: RBC responses to hypoxia and oxidant stress
regulate hemolysis, an etiological contributor to physio/pathological adaptati...

## Key facts

- **NIH application ID:** 10790182
- **Project number:** 2R01HL146442-06
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Angelo D'Alessandro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $724,266
- **Award type:** 2
- **Project period:** 2019-08-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10790182

## Citation

> US National Institutes of Health, RePORTER application 10790182, The role of ferroptosis in red cell aging in vivo and in vitro (2R01HL146442-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10790182. Licensed CC0.

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