Tangeretin mitigates ulcerative colitis by improving BMAL1-mediated intestinal barrier function

Nov 7, 2025Biochemical pharmacology

Tangeretin may ease ulcerative colitis by improving daily rhythm-controlled gut barrier function

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Abstract

Prophylactic tangeretin (TAN) administration significantly alleviated colitis severity in a murine model of ulcerative colitis.

TAN restored locomotor rhythms and reversed disruptions in the expression of several clock genes associated with the intestinal circadian rhythm.
The treatment also reduced levels of inflammatory cytokines such as Il-6 and Il-1β, indicating a potential anti-inflammatory effect.
TAN enhanced the expression and rhythmicity of BMAL1, which is linked to its therapeutic effects in alleviating ulcerative colitis.
The protective effect of TAN was lost in mice lacking BMAL1 specifically in the intestines, highlighting its critical role.
In vitro experiments showed that knocking down BMAL1 eliminated TAN's ability to suppress inflammation and promote barrier repair in intestinal cells.
Timing of TAN administration influenced its effectiveness, with doses given at ZT2 showing significant improvement in symptoms compared to ZT14.

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Ulcerative colitis (UC), a chronic inflammatory bowel disease associated with circadian rhythm disruption, presents a critical need for novel therapeutic strategies. While the natural flavonoid tangeretin (TAN) exhibits anti-inflammatory properties, its effect of alleviating UC and the mechanism through intestinal circadian clock modulation remains unclear. Using a dextran sulfate sodium (DSS)-induced murine colitis model, we demonstrated that Prophylactic TAN administration significantly alleviated colitis severity, restored locomotor rhythms, and reversed UC-induced disruptions in colonic clock gene oscillations (Bmal1, Per1/2, Cry1/2, Dbp, Rev-erbα, and Rorα), inflammatory cytokines (Il-6 and Il-1β), and tight junction proteins (ZO-1 and Occludin). Importantly, TAN robustly enhanced the expression and rhythmicity of BMAL1, which mechanistically drove its therapeutic effects. The critical role of BMAL1 was confirmed by the abolished protective effect of TAN in intestine specific Bmal1 knockout (Bmal1) mice. In vitro studies in MODE-K cells further demonstrated that siRNA-mediated Bmal1 knockdown abolished TAN-mediated suppression of inflammation and barrier repair in lipopolysaccharide (LPS) treated MODE-K cells. Dual-luciferase reporter assays validated that BMAL1 directly enhanced the Zo-1 and Occludin promoter activities. Notably, TAN exhibited chronotherapeutic efficacy, with ZT2 administration significantly improving UC symptoms, whereas ZT14 dosing showed minimal benefits. In conclusion, TAN ameliorates UC by upregulating BMAL1-dependent inflammation suppression and barrier integrity enhancement. This study underscores circadian clock modulation as a promising strategy for UC management and provides a mechanistic foundation for optimizing timed dosing regimens in clinical translation. iKO

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Tangeretin mitigates ulcerative colitis by improving BMAL1-mediated intestinal barrier function

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