# Characterizing the Regulation of Ferroptosis

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $99,280

## Abstract

Project Summary/Abstract
Ferroptosis is a non-apoptotic cell death process that can suppress tumor formation and
contribute to disease pathology. The long-term objective of this research is to understand the
molecular regulation of ferroptosis. Ferroptosis is thought to occur through a stereotypical and
invariant lipid-dependent mechanism. However, in new preliminary studies we have uncovered
evidence for two different forms of ferroptosis defined by unique genetic regulation and metabolic
alterations. We find that ferroptosis triggered by direct inactivation of the enzyme GPX4 requires
the function of the lipid metabolic enzyme ACSL4. A second sub-type of ferroptosis, triggered by
cystine deprivation, does not require ACSL4 or related lipid metabolic enzymes and instead relies
on a novel set of genes. Guided by these new preliminary data, our central hypothesis is that
ferroptosis can be executed by two fundamentally distinct mechanisms. We will test this
hypothesis by pursuing three specific aims: (i) defining the role of ACSL4 and related lipid
metabolic enzymes in promoting ferroptosis in response to direct GPX4 inhibition, (ii) identifying
cellular and molecular features that distinguish the two ferroptosis mechanisms in vitro and in
vivo, and (iii) defining genes and processes that regulate ACSL4-independent ferroptosis in
response to cystine deprivation. These studies will be carried out using cutting-edge chemical,
genetic, functional genomic, lipidomic, and imaging tools and methods. This research will advance
our fundamental understanding of ferroptosis, with the ultimate goal of improving human health.

## Key facts

- **NIH application ID:** 11099451
- **Project number:** 3R01GM122923-07S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Scott Dixon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $99,280
- **Award type:** 3
- **Project period:** 2017-09-05 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11099451

## Citation

> US National Institutes of Health, RePORTER application 11099451, Characterizing the Regulation of Ferroptosis (3R01GM122923-07S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11099451. Licensed CC0.

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