# Elucidating the relationship between lipid droplets, lipid metabolism, and lipotoxicity

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2021 · $317,038

## Abstract

Ferroptosis is a regulated form of lipotoxic cell death that involves iron-dependent generation of
reactive oxygen species (ROS) and the accumulation of oxidatively damaged lipids (e.g. lipid
peroxides). Ferroptosis has been implicated in the etiology of degenerative diseases, such as
neurodegeneration associated with iron accumulation. Cells contain a protective pathway in which
the glutathione-dependent peroxidase GPX4 repairs lipid peroxides and blocks cell death.
Targeted induction of ferroptosis by inhibiting GPX4 has proven to be an efficacious treatment in
in vitro and in vivo models of cancer, including drug-resistant forms of cancer. Despite the
excitement from these recent findings, our understanding of the mechanisms underlying
ferroptosis remains limited. Furthermore, many cancer cells are resistant to ferroptosis and the
mechanisms of ferroptosis resistance in cancer remains mostly unknown. To overcome this
critical gap in knowledge, we performed a synthetic lethal, whole-genome CRISPR screen to
identify factors that protect cancer cells from ferroptosis. Our findings identify the lipid droplet
oxidoreductase AIFM2 as a key factor that promotes ferroptosis resistance in cancer. Deletion of
AIFM2 dramatically sensitizes cells to ferroptosis and AIFM2 levels correlate with cancer
resistance across hundreds of cancer lines, indicating that AIFM2 is a biomarker of ferroptosis
resistance and suggesting that it is broadly involved in ferroptosis resistance across many types
of cancer. Our proposed research builds on our discovery and employs a combination of
functional genomic, cell biology, and biochemistry strategies to achieve the following goals: 1)
elucidate the mechanism by which AIFM2 prevents lipid damage and ferroptosis, 2) define the
relationship between lipid droplets, fatty acid metabolism, and ferroptosis, and 3) identify new
factors involved in protecting cancer cells from ferroptosis. These goals are potentially
transformative because they focus on new mechanisms of ferroptosis resistance in cancer cells
that act in parallel to the canonical glutathione-based protective system.

## Key facts

- **NIH application ID:** 10069387
- **Project number:** 5R01GM112948-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** JAMES A OLZMANN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $317,038
- **Award type:** 5
- **Project period:** 2014-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10069387

## Citation

> US National Institutes of Health, RePORTER application 10069387, Elucidating the relationship between lipid droplets, lipid metabolism, and lipotoxicity (5R01GM112948-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10069387. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*