# Gpx4 and ferroptosis inhibition in retarding ALS

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2020 · —

## Abstract

Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron degenerative
disease, in which motor neuron degeneration and death result in progressive paralysis and
eventual death by respiratory failure. ALS is a particular concern for veterans as several studies
indicated that military service is associated with increased risk of ALS. At present, there are no
effective treatments for this debilitating disease and the development of effective therapies is
impeded by the lack of suitable targets, particularly for sporadic ALS, which represents the
majority cases that do not have identifiable genetic causes. Glutathione peroxidase 4 (Gpx4) is a
selenoprotein glutathione peroxidase important in protecting membranes against oxidative
damage. Recently, Gpx4 was identified as a key inhibitor of ferroptosis, an oxidative, iron-
dependent cell death mechanism different from other cell death mechanisms such as apoptosis.
Serendipitously, we discovered that Gpx4 is a key protector of spinal motor neurons. In addition,
our preliminary results indicated that overexpression of Gpx4 extended lifespan of ALS mice. Our
preliminary results further suggested that the ferroptosis inhibition function of Gpx4 is important
for motor neuron protection. Built upon these exciting results, this project is designed to test the
therapeutic potential of Gpx4 overexpression and ferroptosis inhibition for ALS. The overall
hypothesis to be tested in this project is: Gpx4 overexpression and ferroptosis inhibition can
ameliorate motor neuron degeneration and retard disease of ALS. The hypothesis will be tested
by three specific aims. Aim 1 is to determine whether Gpx4 overexpression improves locomotor
function and attenuates motor neuron degeneration in ALS mice. Aim 2 is to examine the role of
ferroptosis inhibition in retarding disease in ALS mice. Aim 3 is to determine the effect of Gpx4
overexpression mediated by viral delivery in retarding disease of ALS mice. The results from this
project will provide novel insights into the mechanism of motor neuron degeneration in ALS, and
importantly, could lead to new therapeutic strategies for ALS.

## Key facts

- **NIH application ID:** 9898290
- **Project number:** 5I01BX003507-03
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** QITAO RAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898290

## Citation

> US National Institutes of Health, RePORTER application 9898290, Gpx4 and ferroptosis inhibition in retarding ALS (5I01BX003507-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898290. Licensed CC0.

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