ArticleNature metabolism2025
Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD.
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Article in Nature metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31citing papers in PubMed
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Who cites it
31 citing papers in PubMed.
- Article
- BRD4 contributes to the cytokine-induced acquisition of an IL-13RA2-positive inflammatory fibroblast phenotype.Journal of Crohn's & colitis · 2026Article
- Iron-addicted colorectal cancers exploit heme-complex II axis to resist oxidative cell death.Cell metabolism · 2026Article
- Erythritol Exacerbates DSS-Induced Colitis and Influences Behavioral Responses in Mice Through Gut Microbiota and Metabolic Alterations.Microorganisms · 2026Article
- Targeting the NR3C1-ACSL4 Axis Triggers Ferroptosis to Overcome Radioresistance in Prostate Cancer.Cancer science · 2026Article
- The biphasic interactions between ferroptosis and oxidative stress: from molecular mechanisms to disease interventions.Molecular biology reports · 2026Review
- Rational design of FAP-targeted sEVs delivered by microneedles for precision treatment of hypertrophic scars via ferroptosis in hypertrophic scar fibroblasts.Materials today. Bio · 2026Article
- Monocyte-Derived Macrophage Ferroptosis Amplifies Cholangitis in Primary Biliary Cholangitis via a Calpain/ACSL4 Axis.Biomedicines · 2026Article
- Fibroblast-specificAmerican journal of physiology. Gastrointestinal and liver physiology · 2026Article
- Selenium Induces Ferroptosis in Colorectal Cancer Cells via Direct Interaction with Nrf2 and Gpx4.Biological trace element research · 2026Article
- Ferroptosis shapes ILC2 responses in inflammatory bowel disease.Cellular & molecular immunology · 2026Article
- Ketogenic diet exacerbates DSS-induced colitis through a β-hydroxybutyrate-Thomasclavelia spiroformis-γδ17 T cell axis in mice.Nature communications · 2026Article
- CuET promotes cuproptosis and ferroptosis of lung cancer cells by interacting directly with polyunsaturated phospholipids.iScience · 2026Article
- Targeted intestinal barrier repairActa pharmaceutica Sinica. B · 2026Article
- Multifunctional Cu-doped MnMaterials today. Bio · 2026Article
- Oral colon targeted curcumin-based nanocomposite inulin hydrogel for alleviating intestinal inflammation and dysbiosis.Journal of nanobiotechnology · 2026Article
- GHRHR Deficiency Enhances Retinal Ganglion Cell Survival and Visual Functions in Experimental Glaucoma by Inhibiting Ferroptosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Danthron Attenuates Intestinal Inflammation by Modulating Oxidative Stress via the EGFR-PI3K-AKT and Nrf2-HO-1 Pathways.Antioxidants (Basel, Switzerland) · 2026Article
- Inflammatory bowel diseases: pathological mechanisms and therapeutic perspectives.Molecular biomedicine · 2026Review
- Biomimetic Layered Double Hydroxide-Molybdenum Disulfide Encapsulated with Bovine Serum Albumin: A Multifaceted Nanotherapy for Inflammatory Bowel Disease.Biomaterials research · 2026Article
Corrections and comments
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Authors and funding
27 authors.
Wesley Huang *Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0003-0551-8397
Yuezhong Zhang *Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Nupur K DasDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-5652-1134
Sumeet SolankiDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Chesta JainDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Marwa O El-DeranyDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Imhoi KooDepartment of Veterinary and Biomedical Sciences, Pennsylvania State University, State College, PA, USA.ORCID http://orcid.org/0000-0002-5816-0627
Hannah N BellDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Noora AabedDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Rashi SinghalDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0003-2685-5667
Cristina CastilloDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0001-6125-1813
Kathryn BuscherDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Yinzhi YingDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
James DimitroffDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Ankit SharmaDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Jiaqi ShiDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0003-4893-1587
Simon P HoganDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Michael K DameDepartment of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0003-3760-1654
Peter D R HigginsDepartment of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
Justin A ColacinoDepartment of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-5882-4569
Tae Gyu OhDepartment of Oncology Science, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA.ORCID http://orcid.org/0000-0002-2756-3546
Jason R SpenceDepartment of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0001-7869-3992
Andrew D PattersonDepartment of Veterinary and Biomedical Sciences, Pennsylvania State University, State College, PA, USA.ORCID http://orcid.org/0000-0003-2073-0070
Andrew S GreenbergHuman Nutrition Research Center on Aging at Tufts University, Tufts University School of Medicine, Boston, MA, USA.ORCID http://orcid.org/0000-0001-5062-387X
Joel K GreensonDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Asma NusratDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Yatrik M ShahDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. shahy@umich.edu.ORCID http://orcid.org/0000-0002-2487-4816
Funding
XenograftP30CA046592 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Eric R. Fearon · 1988 to 2026
$178.2MTransgenic CoreP30DK046200 · NIDDK · TUFTS MEDICAL CENTER · PI HU, FRANK B · 1992 to 2021
$25.0MStrategic Vision & Impact on Environmental HealthP30ES017885 · NIEHS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Dana Dolinoy · 2011 to 2026
$21.3MRegulation of intestinal epithelial barrier function by intercellular junction proteins in health and diseaseR01DK059888 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ASMA NUSRAT · 2001 to 2026
$10.5MConsortium on Intestinal Regeneration and Fetal Reversion: from Atlas to TherapyRC2DK140862 · NIDDK · CEDARS-SINAI MEDICAL CENTER · PI SARAH E BLUTT, DARIO BOFFELLI · 2024 to 2026
$6.0MControl of iron absorption by intestinal HIF2 in iron and hematological disordersR01DK095201 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2012 to 2025
$5.7MThe role of HIF2alpha in colon carcinogenesisR01CA148828 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2010 to 2025
$5.2MDiversity SupplementR01ES028802 · NIEHS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Justin Adam Colacino · 2018 to 2026
$4.8MEnvironmental Chemical Impact on the Host-Microbiome InteractionR35ES035027 · NIEHS · PENNSYLVANIA STATE UNIVERSITY, THE · PI Andrew Patterson · 2023 to 2026
$3.6MUnderstanding the mechanisms of iron addiction in colon cancerR01CA245546 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2020 to 2024
$2.3MDefining epigenetic signaling to reshape pancreatic tumor microenvironmentR37CA262209 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Jiaqi Shi · 2022 to 2026
$2.3MHuman iPSC intestine mimetics with integrated mesenchymal, endothelial and enteric nervous tissueR01DK137806 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Jason Spence · 2024 to 2026
$1.5MNCI NIH HHS P30 CA046592NCI NIH HHS R01 CA148828NCI NIH HHS R01 CA245546NCI NIH HHS R21 CA273646NCI NIH HHS R37 CA262209NIDDK NIH HHS F30 DK131851NIDDK NIH HHS P30 DK046200NIDDK NIH HHS R01 DK059888NIDDK NIH HHS R01 DK095201NIDDK NIH HHS R01 DK137806NIDDK NIH HHS RC2 DK140862NIEHS NIH HHS P30 ES017885NIEHS NIH HHS R01 ES028802NIEHS NIH HHS R35 ES035027NIH HHS S10 OD021750U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA148828U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA245546U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R21CA273646U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R37CA262209U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) F30DK131851U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) P30DK046200U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) R01DK095201U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) R01DK137806U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) RC2DK140862U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS) P30ES017885U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS) R35ES035027U.S. Department of Health & Human Services | NIH | NIH Office of the Director (OD) S10OD021750
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.
Indexed as
Coenzyme A LigasesEpithelial CellsFerroptosisFibroblastsInflammatory Bowel DiseasesLipid MetabolismAnimalsDisease Models, AnimalHumansIntestinal MucosaLong-Chain-Fatty-Acid-CoA LigaseMiceMice, Inbred C57BLReactive Oxygen SpeciesAcsl4 protein, mouseCoenzyme A LigasesLong-Chain-Fatty-Acid-CoA LigaseReactive Oxygen Species
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