# The role of membrane lipid remodeling in cancer cell ferroptosis sensitivity

> **NIH NIH F31** · STANFORD UNIVERSITY · 2023 · $40,168

## Abstract

Project Summary
 Phospholipids are the major component of biological membranes and are essential for all cellular life.
Phospholipid metabolism is altered in tumor cells. However, there are currently no approved anti-cancer drugs
that target phospholipid metabolic enzymes. Inhibition of survival-promoting phospholipid metabolic enzymes
would present a novel strategy to induce cell death in cancer cells. Ferroptosis is a form of cell death that is
dependent on membrane phospholipid composition. Ferroptosis is caused by direct damage to membrane
phospholipids by reactive oxygen species (ROS). Our group and others have found that the tail groups of
phospholipids can determine a cell’s sensitivity to ferroptosis. Tail groups with multiple double-bonds
(polyunsaturated fatty acids, PUFAs) are more likely to be oxidized than those with only one double bond
(monounsaturated fatty acid, MUFA). Therefore, cells with greater levels of PUFAs are more susceptible to death
by ferroptosis, whereas cells with greater levels of MUFAs resist ferroptosis. This is particularly relevant in cancer
treatment because induction of ferroptosis is emerging as an effective strategy to kill cancer cells. In preliminary
studies, I find that Membrane-Bound O-Acyltransferase 1 (MBOAT1) is a novel ferroptosis regulating gene.
MBOAT1 is a lipid metabolic gene that incorporates MUFAs into phospholipids. MBOAT1 gene expression or
copy number is elevated in multiple tumor types, and higher expression of MBOAT1 is correlated with poor
prognosis in pancreatic cancer patients. I find that inhibiting MBOAT1 increases cancer cells’ susceptibility to
ferroptosis. Therefore, MBOAT1 represents a novel target for cancer treatment. Based on these findings, I
hypothesize that inhibition of MBOAT1 sensitizes cells to ferroptosis by altering phospholipid
metabolism. In Aim 1, I will elucidate the role of MBOAT1 in ferroptosis sensitivity and in phospholipid
metabolism. Then in Aim 2, I will test the combination of MBOAT1 inhibition and ferroptosis induction as a novel
strategy for the treatment of cancer in vivo. Overall, this work will have biological significance by characterizing
the function and regulation of MBOAT1, and clinical significance by establishing MBOAT1 as a novel target to
induce ferroptosis in cancer cells.

## Key facts

- **NIH application ID:** 10469334
- **Project number:** 5F31CA265146-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jason Rodencal
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $40,168
- **Award type:** 5
- **Project period:** 2021-09-01 → 2023-12-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469334

## Citation

> US National Institutes of Health, RePORTER application 10469334, The role of membrane lipid remodeling in cancer cell ferroptosis sensitivity (5F31CA265146-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10469334. Licensed CC0.

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