Authors:

Grace O. Caris

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Inflammatory Bowel Disease (IBD) is a highly prevalent and debilitating chronic inflammatory disorder of the gastrointestinal tract with no definitive cure. Increased reactive oxygen species (ROS) levels are considered as a hallmark of IBD progression, however, broad antioxidant strategies limit the benefits of clinical usage. Lipid peroxidation is the fundamental mechanism underlying ferroptosis, an iron-dependent form of programmed cell death. Acyl-CoA Synthase long-chain family 4 (ACSL4) promotes the incorporation of polyunsaturated fatty acids (PUFAs) into membrane phospholipids, which are highly susceptible to lipid peroxidation. Increased ACSL4 expression was observed in IBD lesions, especially in fibroblast populations. Notably, our previous findings demonstrated that fibroblast ACSL4 is essential to IBD pathophysiology, as fibroblast-specific overexpression of ACSL4 worsened colitis progress, whereas fibroblast-specific deletion of ACSL4 preserved colonic homeostasis in murine models of colitis [1]. However, the mechanisms regulating ACSL4 expression in fibroblasts during IBD remain unclear. We examined factors relevant to IBD pathology, including inflammatory cytokines, hypoxia, and iron. Treatment with cytokines (e.g., IFNy, TNFa, IL-18, and IL-10) or exposure to hypoxia (2% Oz) did not induce ACSL4 expression in fibroblast cell lines or primary murine colonic fibroblasts, as assessed by Western blot and qPCR. In contrast, iron robustly induced ACSL4 gene and protein expression in a time- and dose-dependent manner, with ferric ammonium citrate (FAC, 100 yM) at 24 hours producing peak induction. Moreover, the iron chelator deferoxamine (DFO) abrogated FAC-induced ACSL4 expression, supporting an iron-specific regulatory mechanism. Given that IBD lesions are characterized by a robust tissue iron accumulation, we hypothesize that iron drives fibroblast ACSL4 expression, thereby contributing to IBD pathophysiology. These findings provide new mechanistic insight into IBD etiology and suggest potential therapeutic targets for further investigation.

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Chicago Area Undergraduate Research Symposium

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Co-authors:

Grace O. Caris