Cellular and molecular gastroenterology and hepatology · 2026
Suppressing α-1,6-Fucosyltransferase With a Novel Small Molecule Inhibitor Ameliorates Inflammation in Murine T-Cell-Mediated Colitis Models.
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Asakura Akiko, Shinzaki Shinichiro, Manabe Yoshiyuki, Hizume Koki, Tsujii Yuri, Tashiro Taku, Amano Takahiro, Tani Mizuki, Otake-Kasamoto Yuriko, Yoshihara Takeo, Uema Ryotaro, Tsujii Yoshiki, Iijima Hideki, Kamada Yoshihiro, Okuzaki Daisuke, Motooka Daisuke, Fukuda Tomohiko, Kudo Takashi, Takahashi Satoru, Gu Jianguo, Miyoshi Eiji, Fukase Koichi, Hayashi Yoshito, Takehara Tetsuo
Аннотация
BACKGROUND & AIMS: Inflammatory bowel disease 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-the sole glycosyltransferase catalyzing core fucosylation of N-glycans in mammals-as an anti-inflammatory agent.
METHODS: α-1,6-Fucosyltransferase inhibitor efficacy was evaluated in 2 murine models: a trinitrobenzene sulfonic acid-induced colitis model and a naive CD4+ T-cell adoptive transfer model using recombination activating gene 2 (Rag2)-deficient mice. Amelioration of trinitrobenzene sulfonic acid-induced colitis by the α-1,6-fucosyltransferase inhibitor was also evaluated in LckcreFut8fl/fl mice in which α-1,6-fucosyltransferase is conditionally abrogated in T cells. Splenic CD4+ T cells from wild-type mice were treated with the α-1,6-fucosyltransferase inhibitor to evaluate its effects on cell signaling, cytokine production, and T helper 1, 2, and 17 differentiation. In vivo safety was assessed in wild-type mice.
RESULTS: Oral administration of the α-1,6-fucosyltransferase inhibitor effectively decreased T-cell core fucosylation and ameliorated trinitrobenzene sulfonic acid-induced colitis and colitis induced by adoptive T-cell transfer. These clinical effects were accompanied by decreased T helper 1 and 2 cytokine production from CD4+ T cells. Trinitrobenzene sulfonic acid-induced colitis was attenuated in LckcreFut8fl/fl mice, demonstrating that the ameliorative effect of α-1,6-fucosyltransferase inhibition is directly mediated by T cells. In vitro, the inhibitor suppressed T-cell signal transduction and T helper 1, 2, and 17 cell differentiation. No apparent hepatorenal toxicity or intestinal mucus layer disruption was observed.
CONCLUSIONS: α-1,6-Fucosyltransferase inhibition modulated T-cell core fucosylation and reduced inflammation in murine colitis models without apparent toxicity, indicating that targeting α-1,6-fucosyltransferase may offer a novel therapeutic approach for inflammatory bowel disease by disrupting proinflammatory T-cell responses.
METHODS: α-1,6-Fucosyltransferase inhibitor efficacy was evaluated in 2 murine models: a trinitrobenzene sulfonic acid-induced colitis model and a naive CD4+ T-cell adoptive transfer model using recombination activating gene 2 (Rag2)-deficient mice. Amelioration of trinitrobenzene sulfonic acid-induced colitis by the α-1,6-fucosyltransferase inhibitor was also evaluated in LckcreFut8fl/fl mice in which α-1,6-fucosyltransferase is conditionally abrogated in T cells. Splenic CD4+ T cells from wild-type mice were treated with the α-1,6-fucosyltransferase inhibitor to evaluate its effects on cell signaling, cytokine production, and T helper 1, 2, and 17 differentiation. In vivo safety was assessed in wild-type mice.
RESULTS: Oral administration of the α-1,6-fucosyltransferase inhibitor effectively decreased T-cell core fucosylation and ameliorated trinitrobenzene sulfonic acid-induced colitis and colitis induced by adoptive T-cell transfer. These clinical effects were accompanied by decreased T helper 1 and 2 cytokine production from CD4+ T cells. Trinitrobenzene sulfonic acid-induced colitis was attenuated in LckcreFut8fl/fl mice, demonstrating that the ameliorative effect of α-1,6-fucosyltransferase inhibition is directly mediated by T cells. In vitro, the inhibitor suppressed T-cell signal transduction and T helper 1, 2, and 17 cell differentiation. No apparent hepatorenal toxicity or intestinal mucus layer disruption was observed.
CONCLUSIONS: α-1,6-Fucosyltransferase inhibition modulated T-cell core fucosylation and reduced inflammation in murine colitis models without apparent toxicity, indicating that targeting α-1,6-fucosyltransferase may offer a novel therapeutic approach for inflammatory bowel disease by disrupting proinflammatory T-cell responses.