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Updated: Sep 18, 2025
A Fluorescence-based Assay for Characterization and Quantification of Lipid Droplet Formation in Human Intestinal Organoids
Published on: October 13, 2019
Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD
Wesley Huang1,2,3, Yuezhong Zhang1,4,5, Nupur K Das1
1Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Abstract:
Increased reactive oxygen species (ROS) levels are a hallmark of inflammatory bowel disease (IBD) and constitute a major mechanism of epithelial cell death. Approaches to broadly inhibit ROS have had limited efficacy in treating IBD. Here we show that lipid peroxidation contributes to the pathophysiology of IBD by promoting ferroptosis, an iron-dependent form of programmed cell death. Mechanistically, we provide evidence of heterocellular crosstalk between intestinal fibroblasts and epithelial cells. In IBD tissues and mouse models of chronic colitis, acyl-CoA synthetase long-chain family 4 (ACSL4) is overexpressed in fibroblasts. ACSL4 in fibroblasts reprograms lipid metabolism and mediates intestinal epithelial cell sensitivity to ferroptosis. In mouse models, overexpressing ACSL4 in fibroblasts results in increased intestinal epithelial ferroptosis and worsened colitis, while pharmacological inhibition or deletion of fibroblast ACSL4 ameliorates colitis. Our work provides a targeted approach to therapeutic antioxidant treatments for IBD.
Insights
Inflammatory bowel disease (IBD) involves cell death. Targeting fibroblast ACSL4 reduces lipid peroxidation and ferroptosis, offering a new therapeutic strategy for IBD.
Area of Science:
- Gastroenterology
- Cell Biology
- Biochemistry
Background:
- Reactive oxygen species (ROS) increase in inflammatory bowel disease (IBD), causing epithelial cell death.
- Broad ROS inhibition shows limited efficacy in IBD treatment.
- Lipid peroxidation and ferroptosis are implicated in IBD pathophysiology.
Purpose of the Study:
- To investigate the role of lipid peroxidation and ferroptosis in IBD.
- To elucidate the mechanism of heterocellular crosstalk between fibroblasts and epithelial cells in IBD.
- To identify potential therapeutic targets for IBD.
Main Methods:
- Analysis of IBD tissues and chronic colitis mouse models.
- Assessment of acyl-CoA synthetase long-chain family 4 (ACSL4) expression in fibroblasts.
- Investigation of fibroblast ACSL4's role in lipid metabolism and epithelial cell ferroptosis.
- Pharmacological inhibition and genetic deletion of fibroblast ACSL4 in mouse models.
Main Results:
- ACSL4 is overexpressed in fibroblasts in IBD tissues and colitis models.
- Fibroblast ACSL4 reprograms lipid metabolism, increasing epithelial cell ferroptosis sensitivity.
- Fibroblast-specific ACSL4 overexpression exacerbates colitis.
- Inhibition or deletion of fibroblast ACSL4 ameliorates colitis in mouse models.
Conclusions:
- Lipid peroxidation, mediated by fibroblast ACSL4, promotes ferroptosis and exacerbates IBD.
- Targeting fibroblast ACSL4 offers a novel, targeted therapeutic strategy for IBD.
- This approach provides a new avenue for antioxidant-based IBD treatments.
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