# Investigating the regulation of cancer cell death by NFE2L1

> **NIH NIH F31** · STANFORD UNIVERSITY · 2024 · $42,468

## Abstract

Project Summary
Resistance to therapy is responsible for 90% of cancer patient mortality. Our understanding of how cancer
cells resist therapy-induced death is limited. My goal is to better understand the molecular mechanisms of
cancer cell therapy resistance, with an eye toward improving therapy. Identifying and characterizing novel
resistance mechanisms should facilitate the design of more effective cancer therapies. Immunotherapy and
ionizing radiation are two common cancer therapies. These therapies kill cancer cells, in part, via ferroptosis:
a non-apoptotic cell death mechanism characterized by lipid peroxidation. Sensitizing cancer cells to
ferroptosis may improve the efficacy of these and other cancer therapies. To effectively sensitize cancer cells
to ferroptosis, we must identify how cancer cells normally resist ferroptosis. However, the mechanisms by
which cancer cells resist ferroptosis are poorly understood. I recently showed that the transcription factor
nuclear factor erythroid 2 like 1 (NFE2L1, or NRF1) is required to protect cancer cells from ferroptosis. My
overarching hypothesis is that NFE2L1 is central to an important pathway promoting ferroptosis
resistance in cancer cells. The goal of this research, as part of my overall training plan, is to test this
hypothesis and determine how NFE2L1 protects cancer cells from ferroptosis. Ultimately, this research has
the potential to inform advances in cancer therapy. I propose two Specific Aims. In Aim 1, I will test whether
certain post-translational modifications of NFE2L1 are required for ferroptosis resistance. These studies will
be conducted using genetic and pharmacologic approaches to perturb NFE2L1 N-glycosylation and cleavage
and assess the effects on ferroptosis sensitivity. To support the successful execution of this aim, I will be
trained in glycobiology by my co-sponsor, Dr. Carolyn Bertozzi, who pioneered this field. In Aim 2, I will
elucidate the role of nicotinamide N-methyltransferase (NNMT) in ferroptosis resistance. Preliminary data
suggest that NNMT, which encodes an enzyme involved in nicotinamide adenine dinucleotide metabolism, is
a direct target of NFE2L1. I hypothesize that NNMT regulates cancer cell ferroptosis sensitivity by altering
redox homeostasis. Through my proposed experiments, I will determine whether NNMT is a direct target of
NFE2L1. I will also assess ferroptosis sensitivity in cells in which NNMT is knocked out or overexpressed.
Mass spectrometry will be used to measure the abundance of redox molecules in these cell lines to analyze
the role of NNMT in ferroptosis-related redox regulation. I will be trained in mass spectrometry by my
collaborator, Dr. Monther Abu-Remaileh, who is an expert in metabolomics. With the guidance of my expert
team of mentors at Stanford University, my proposed experiments will elucidate this novel pathway promoting
cancer cell ferroptosis evasion and identify possible strategies to minimize cancer therapy resistance.

## Key facts

- **NIH application ID:** 10997255
- **Project number:** 1F31CA284784-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** MAGDALENA MURRAY
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,468
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997255

## Citation

> US National Institutes of Health, RePORTER application 10997255, Investigating the regulation of cancer cell death by NFE2L1 (1F31CA284784-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10997255. Licensed CC0.

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