Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD

Wesley Huang^#^{1

2

3}, Yuezhong Zhang^#^{1

4

5}, Nupur K Das¹, Sumeet Solanki¹, Chesta Jain¹, Marwa O El-Derany^{1

6}, Imhoi Koo⁷, Hannah N Bell¹, Noora Aabed¹, Rashi Singhal¹, Cristina Castillo¹, Kathryn Buscher¹, Yinzhi Ying¹, James Dimitroff¹, Ankit Sharma⁸, Jiaqi Shi⁸, Simon P Hogan⁸, Michael K Dame^{9

10}, Peter D R Higgins⁹, Justin A Colacino¹¹, Tae Gyu Oh¹², Jason R Spence^{9

10}, Andrew D Patterson⁷, Andrew S Greenberg¹³, Joel K Greenson⁸, Asma Nusrat⁸, Yatrik M Shah^{14

15}

Affiliations

¹ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
² Department of Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA.
³ Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA.
⁴ The Second Xiangya Hospital, Central South University, Changsha, China.
⁵ M.D./Ph.D. Dual-degree program, Xiangya Medical School-Central South University and University of Michigan Medical School-University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
⁷ Department of Veterinary and Biomedical Sciences, Pennsylvania State University, State College, PA, USA.
⁸ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁹ Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
¹¹ Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
¹² Department of Oncology Science, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA.
¹³ Human Nutrition Research Center on Aging at Tufts University, Tufts University School of Medicine, Boston, MA, USA.
¹⁴ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. shahy@umich.edu.
¹⁵ Department of Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA. shahy@umich.edu.

^# Contributed equally.

PMID: 40571769
PMCID: PMC12444769 (available on 2026-07-01)
DOI: 10.1038/s42255-025-01313-x

Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD

Wesley Huang et al. Nat Metab. 2025 Jul.

. 2025 Jul;7(7):1358-1374.

doi: 10.1038/s42255-025-01313-x. Epub 2025 Jun 26.

Authors

Affiliations

¹ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
² Department of Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA.
³ Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA.
⁴ The Second Xiangya Hospital, Central South University, Changsha, China.
⁵ M.D./Ph.D. Dual-degree program, Xiangya Medical School-Central South University and University of Michigan Medical School-University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
⁷ Department of Veterinary and Biomedical Sciences, Pennsylvania State University, State College, PA, USA.
⁸ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁹ Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
¹¹ Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
¹² Department of Oncology Science, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA.
¹³ Human Nutrition Research Center on Aging at Tufts University, Tufts University School of Medicine, Boston, MA, USA.
¹⁴ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. shahy@umich.edu.
¹⁵ Department of Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA. shahy@umich.edu.

^# Contributed equally.

PMID: 40571769
PMCID: PMC12444769 (available on 2026-07-01)
DOI: 10.1038/s42255-025-01313-x

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.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

1. Tavakoli P et al. A review of inflammatory bowel disease: a model of microbial, immune and neuropsychological integration. Public Health Rev. 42, 1603990 (2021). - PMC - PubMed
1. Huang W, Aabed N & Shah YM Reactive oxygen species and ferroptosis at the nexus of inflammation and colon cancer. Antioxid. Redox Signal 39, 551–568 (2023). - PMC - PubMed
1. Chen L et al. The antioxidant procyanidin reduces reactive oxygen species signaling in macrophages and ameliorates experimental colitis in mice. Front. Immunol 8, 1910 (2017). - PMC - PubMed
1. Ananthakrishnan AN et al. Statin use is associated with reduced risk of colorectal cancer in patients with inflammatory bowel diseases. Clin. Gastroenterol. Hepatol 14, 973–979 (2016). - PMC - PubMed
1. Moura FA et al. Antioxidant therapy for treatment of inflammatory bowel disease: does it work? Redox Biol. 6, 617–639 (2015). - PMC - PubMed

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Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD

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Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD

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