# Targeting ferroptosis in cancer therapy

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $469,297

## Abstract

Project Summary
 Studying regulated cell death is critical for our understanding of tumor suppression and development of
novel effective cancer therapy. Ferroptosis, an iron-dependent form of regulated cell death that is induced by
excessive lipid peroxidation, is morphologically and mechanistically distinct from other forms of regulated cell
death such as apoptosis. However, in contrast to our deep understanding of apoptosis, how ferroptosis is
regulated and coordinates with other cellular signaling in tumor suppression remains much less well understood.
There also exists a significant need to translate our understanding of ferroptosis mechanisms into effective
cancer therapies. Our long-term goal is to understand the mechanism(s) of action of anti-neoplastic agents
and/or combinations of agents that target ferroptosis in cancer therapy. The objective of this application is to
determine the role and mechanisms of AMP-activated protein kinase (AMPK), a critical sensor of cellular energy
status, in regulating ferroptosis and the relevance of these regulatory functions to tumor suppression and
treatment. Energy stress depletes ATP and induces cell death. Surprisingly, our recent study revealed that
energy stress can potently suppress ferroptotic cell death through activating AMPK. Cancer cells with high basal
AMPK activation are resistant to ferroptosis, and AMPK inactivation sensitizes such cancer cells to ferroptosis.
Our recent publication and new preliminary data support the central hypothesis that AMPK inhibits ferroptosis
through AMPK-mediated phosphorylation of acetyl-CoA carboxylase (ACC) and biosynthesis of polyunsaturated
fatty acid (PUFA) as well as other unidentified downstream effectors. AMPK can have either tumor-suppressive
or -promoting functions, depending on the context. We further hypothesize that AMPK’s tumor-promoting
function is at least partly mediated by its inhibition of ferroptosis, and combining AMPK inhibitors and ferroptosis
inducers (FINs) is a novel therapeutic strategy for treating AMPK-dependent cancers. To test our hypotheses,
we will pursue the following specific aims: Specific Aim 1: To study the mechanisms by which AMPK inhibits
ferroptosis in cancer cells. Specific Aim 2: To determine the relevance of ferroptosis to AMPK-mediated tumor
development and treatment. It is expected that our proposed studies will clarify how AMPK regulates PUFA
biosynthesis, identify novel regulatory mechanisms of ferroptosis pathways, and reveal a previously
unrecognized function of ferroptosis suppression in AMPK-mediated tumor promotion in cancer. Our proposal is
highly innovative because it focuses on a previously unexplored pathway linking AMPK regulation of ferroptosis
to tumor development. Our proposed studies will have significant impact on both our basic understanding of
ferroptosis and our ability to target AMPK or ferroptosis in cancer treatment.

## Key facts

- **NIH application ID:** 10794965
- **Project number:** 5R01CA269646-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Boyi Gan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $469,297
- **Award type:** 5
- **Project period:** 2023-03-01 → 2028-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10794965

## Citation

> US National Institutes of Health, RePORTER application 10794965, Targeting ferroptosis in cancer therapy (5R01CA269646-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10794965. Licensed CC0.

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