# The role of lipid reprogramming in ferroptotic cell death in inflammatory bowel disease (IBD)

> **NIH NIH F30** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $39,531

## Abstract

ABSTRACT
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory condition of the gut that impacts over a
million people in the U.S. yearly. There are two major forms of IBD, Crohn’s disease (CD) and ulcerative colitis
(UC). Chronic inflammation and unregulated mucosal immune activation lead to epithelial damage in a self-
perpetuated cycle that is difficult to treat, and many patients require surgical resection of the inflamed foci. CD
and UC are histologically distinct, yet the enhanced production of reactive oxygen species (ROS) is a hallmark
for both CD and UC. The increase in ROS is thought to be a major mechanism of epithelial cell death in IBD.
Indeed, mouse models of colitis are highly protected from tissue injury following antioxidant treatment. However,
inhibiting ROS in IBD has only led to modest benefits in disease activity in patients. It is well appreciated that
ROS can induce cell death via both regulated and unregulated cell death pathways and better characterization
of these are needed in IBD. Mining of a large RNA-seq database of IBD, we identified an iron and lipid signature.
Iron-induced lipid peroxidation is a hallmark of a relatively recent described form of cell death termed ferroptosis.
The two most well studied effectors of ferroptosis are the System Xc- transporter and glutathione peroxidase
(GPX)4. System Xc- is a heteromeric amino acid antiporter which mediates the import of extracellular cystine
in exchange for intracellular glutamate. SLC7A11 is the subunit of the dimer with transport activity.
Intracellular cystine is converted to cysteine for production of the antioxidant glutathione. GPX4 utilizes
glutathione to reduce lipid peroxides. Ferroptosis can be synthetically activated via pharmacological or
genetic inhibition of SLC7A11 or GPX4. More recent work has shown that ferroptosis is highly integrated to
cellular lipid metabolism and the long-chain-fatty-acid-CoA ligase (ACSL)4 is a central executioner of
ferroptosis. Deletion of ACSL4 leads to resistance, whereas increased expression leads to susceptibility to
ferroptosis. I show that in acute models of intestinal injury, no ferroptosis is observed. Whereas, ferroptosis is a
major hallmark in IBD patient samples and mouse models of chronic intestinal injury. Interestingly, deletion of
GPX4 or SLC7A11 in intestinal epithelial cells did not increase ferroptosis basally or in acute models of colitis.
However, these mice were highly susceptible in chronic models of intestinal injury. Consistent with these data, I
have shown that ACSL4 is significantly upregulated in IBD, but not acute models of intestinal injury. Building on
the preliminary data, I hypothesize that cellular lipid reprogramming via ACSL4 in chronic inflammation initiates
ferroptosis in IBD. Aim 1 will assess if ferroptosis inhibitors are central protective mechanisms in models of IBD.
Aim 2 will test the translational value of ACSL4 modulation in preclinical models of IBD. The importance...

## Key facts

- **NIH application ID:** 10466181
- **Project number:** 1F30DK131851-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Wesley WeiQiao Huang
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,531
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466181

## Citation

> US National Institutes of Health, RePORTER application 10466181, The role of lipid reprogramming in ferroptotic cell death in inflammatory bowel disease (IBD) (1F30DK131851-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10466181. Licensed CC0.

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