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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年6月26日

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  • Wesley Huang,
  • Yuezhong Zhang,
  • Nupur K. Das,
  • Sumeet Solanki,
  • Chesta Jain,
  • Marwa O. El-Derany,
  • Imhoi Koo,
  • Hannah N. Bell,
  • Noora Aabed,
  • Rashi Singhal,
  • Cristina Castillo,
  • Kathryn Buscher,
  • Yinzhi Ying,
  • James Dimitroff,
  • Ankit Sharma,
  • Jiaqi Shi,
  • Simon P. Hogan,
  • Michael K. Dame,
  • Peter D. R. Higgins,
  • Justin A. Colacino,
  • Tae Gyu Oh,
  • Jason R. Spence,
  • Andrew D. Patterson,
  • Andrew S. Greenberg,
  • Joel K. Greenson,
  • Asma Nusrat,
  • Yatrik M. Shah

摘要

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.