Suppressing FUT8 with a Novel Small Molecule Inhibitor Ameliorates Inflammation in Murine T Cell-mediated Colitis Models.

Authors

Akiko Asakura, Shinichiro Shinzaki, Yoshiyuki Manabe, Koki Hizume, Yuri Tsujii, Taku Tashiro, Takahiro Amano, Mizuki Tani, Yuriko Otake-Kasamoto, Takeo Yoshihara, Ryotaro Uema, Yoshiki Tsujii, Hideki Iijima, Yoshihiro Kamada, Daisuke Okuzaki, Daisuke Motooka, Tomohiko Fukuda, Takashi Kudo, Satoru Takahashi, Jianguo Gu, Eiji Miyoshi, Koichi Fukase, Yoshito Hayashi, Tetsuo Takehara

Published in

Cellular and molecular gastroenterology and hepatology. Pages 101865. Aug 14, 2026. Epub Aug 14, 2026.

Abstract

Inflammatory bowel disease (IBD) involves intractable intestinal inflammation often refractory to current pharmacotherapies. We investigated the therapeutic potential of a novel, orally available inhibitor targeting α-1,6-fucosyltransferase (FUT8)-the sole glycosyltransferase catalyzing core fucosylation of N-glycans in mammals-as an anti-inflammatory agent.
FUT8 inhibitor efficacy was evaluated in two murine models: a trinitrobenzene sulfonic acid (TNBS)-induced colitis model and a naive CD4⁺ T-cell adoptive transfer model using recombination activating gene 2 (Rag2)-deficient mice. Amelioration of TNBS-induced colitis by the FUT8 inhibitor was also evaluated in Lck^creFut8^fl/fl mice in which FUT8 is conditionally abrogated in T cells. Splenic CD4⁺ T cells from wild-type mice were treated with the FUT8 inhibitor to evaluate its effects on cell signaling, cytokine production, and Th1/Th2/Th17 differentiation. In vivo safety was assessed in wild-type mice.
Oral administration of the FUT8 inhibitor effectively decreased T-cell core fucosylation and ameliorated TNBS-induced colitis and colitis induced by adoptive T-cell transfer. These clinical effects were accompanied by decreased Th1 and Th2 cytokine production from CD4⁺ T cells. TNBS-induced colitis was attenuated in Lck^creFut8^fl/fl mice, demonstrating that the ameliorative effect of FUT8 inhibition is directly mediated by T cells. In vitro, the inhibitor suppressed T-cell signal transduction and Th1/Th2/Th17 cell differentiation. No apparent hepatorenal toxicity or intestinal mucus layer disruption was observed.
FUT8 inhibition modulated T-cell core fucosylation and reduced inflammation in murine colitis models without apparent toxicity, indicating that targeting FUT8 may offer a novel therapeutic approach for IBD by disrupting pro-inflammatory T-cell responses.

PMID:
42601022
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

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