# Alzheimer's Administrative Supplement - An antisense RNA-mediated regulatory program that drives cancer metastasis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $403,750

## Abstract

PROJECT SUMMARY
 Ferroptosis is a recently discovered pathway of programmed cell death, which involves iron and reactive
oxygen species (ROS). Ferroptosis is distinct from apoptosis, autophagy and other forms of cell death. While it
was first discovered in cancer, it has now been implicated in several neurologic diseases, including Alzheimer's
disease (AD). Hallmarks of ferroptosis, e.g. lipid peroxidation and iron dysregulation, have long been observed
in brain samples from AD patients. Genetic studies in mouse models of AD also support a substantial role for
ferroptosis in neuronal death. Therefore, there is a clear need for better elucidating the regulatory pathways of
ferroptosis that play a role in AD. We recently discovered a new regulatory program that modulates ferroptotic
cell death in cancer cells. This pathway is especially intriguing as it involves an antisense RNA as the underlying
mater regulator. We have names this antisense RNA NQO1-AS as it is transcribed from a promoter on the
positive strand coinciding with the 3'UTR of gene NQO1. NQO1 is a redox protein and we have shown that the
NQO1-AS modulates the redox state of the cell through binding and stabilization of the NQO1 mRNA. More
importantly, this NQO1-AS/NQO1 regulatory axis plays a role in ferroptosis. We have shown that silencing
NQO1-AS or NQO1 sensitizes cells to ferroptotic cell death following oxidative stress. Having discovered this
new pathway, we asked whether evidence of its activity could be found in other biological systems. Interesting,
we observed a significant reduction in NQO1 mRNA expression and stability in Alzheimer's disease datasets
from the regions of the brain most affected by this pathology. This reduction persisted even in microdissected
samples, which control for general neuronal loss. Given these findings, we see a strong case for the involvement
of the NQO1-NQO1-AS in AD, and therefore we have taken steps to extend our studies in cancer cells to iPSC-
derived neurons in models of Alzheimer's disease. The successful completion of this study will dissect the
possible role of NQO1-mediated ferroptosis in AD and may provide new therapeutic pathways that restore NQO1
activity through synthetic oligos that mimic NQO1-AS and restore higher NQO1 activity.

## Key facts

- **NIH application ID:** 10117474
- **Project number:** 3R01CA240984-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Hani Goodarzi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,750
- **Award type:** 3
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117474

## Citation

> US National Institutes of Health, RePORTER application 10117474, Alzheimer's Administrative Supplement - An antisense RNA-mediated regulatory program that drives cancer metastasis (3R01CA240984-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10117474. Licensed CC0.

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