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Background Intestinal fibrosis represents a debilitating complication of inflammatory bowel disease (IBD) for which effective therapeutic interventions remain scarce. Itaconate, an endogenous immunomodulatory metabolite, has demonstrated potent anti-inflammatory properties. This study aimed to investigate the therapeutic potential of its cell-permeable derivative, 4-octyl itaconate (4-OI), in attenuating intestinal fibrosis using two distinct murine models of chronic colitis.Methods Chronic colitis and associated fibrosis were induced in C57BL/6 mice via cyclic administration of dextran sulfate sodium (DSS) or escalating doses of 2,4,6-trinitrobenzene sulfonic acid (TNBS) over 45 days. Mice received daily treatment with 4-OI or vehicle. Disease progression was assessed by body weight and colon length. Post-euthanasia, colonic tissues underwent histological evaluation (H&E, Masson’s trichrome, Sirius Red, and AB-PAS) and immunohistochemical analysis ( α-SMA, Collagen I, and Vimentin) to quantify inflammation, goblet cell loss, myofibroblast activation, and extracellular matrix (ECM) deposition.Results In both models ( IDDF2026-ABS-0513 Figure 1. Therapeutic effect of 4-OI in the DSS-induced chronic colitis model, IDDF2026-ABS-0513 Figure 2. Therapeutic effect of 4-OI in the TNBS-induced chronic colitis model), 4-OI treatment significantly attenuated weight loss and preserved colonic architectural integrity. Histological analysis showed that 4-OI restored goblet cell populations and reduced mucosal ulceration. Crucially, 4-OI markedly suppressed fibrotic progression, evidenced by reduced collagen deposition in Sirius Red and Masson’s staining. Immunostaining confirmed a robust downregulation of myofibroblast activation markers (α-SMA and Vimentin) and Collagen I expression. Furthermore, 4-OI significantly reversed colon shortening in the TNBS model. These data demonstrate that 4-OI inhibits myofibroblast activation and limits excessive ECM accumulation, regardless of the induction method.Conclusions 4-OI effectively ameliorates intestinal fibrosis in chronic murine colitis by suppressing myofibroblast activation and limiting ECM deposition. These findings suggest that itaconate derivatives represent a promising therapeutic strategy for the management of fibrotic complications in IBD.Abstract IDDF2026-ABS-0513 Figure 1Abstract IDDF2026-ABS-0513 Figure 2