Molecular immunology · 2026
Inhibition of CDK9 improves colonic epithelial dysfunction in DSS-induced ulcerative colitis mice by blocking the IL-6/STAT3 signaling pathway.
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Zhao Wencui, Wu Yanyun, Zhao Nan, Zhang Yan, Liu Lu, Zhang Wei, Zhao Qinglan
Аннотация
BACKGROUND: Ulcerative colitis (UC) is driven by relentless mucosal inflammation and epithelial barrier compromise. Cyclin-dependent kinase 9 (CDK9) governs transcriptional elongation, yet its therapeutic potential in restoring the intestinal barrier via the STAT3 signaling axis remains underexplored.
METHODS: The effects of the selective CDK9 inhibitor, LDC000067 (LDC), in dextran sulfate sodium (DSS)-induced colitis mice and lipopolysaccharide (LPS)-stimulated Caco-2 cells were investigated. Disease severity, barrier ultrastructure, and molecular signaling pathways were assessed via histology, transmission electron microscopy (TEM), nuclear-cytoplasmic fractionation, and immunofluorescence.
RESULTS: LDC administration significantly ameliorated clinical symptoms, preserved colonic length, and mitigated histological injury in DSS-induced mice. Crucially, it protected epithelial ultrastructure and replenished mucin-secreting goblet cells. Mechanistically, CDK9 inhibition suppressed the inflammatory cytokine secretion (particularly IL-6) and inhibited RNAPII Ser2 phosphorylation, thereby attenuating the availability of upstream IL-6, which in turn correlated with reduced phosphorylation and nuclear translocation of STAT3. In vitro experiments corroborated that LDC impeded LPS-induced STAT3 nuclear translocation, consequently rescuing tight junction protein expression (ZO-1, Occludin) and reinforcing transepithelial electrical resistance (TEER).
CONCLUSION: Collectively, LDC alleviates colitis by broadly dampening inflammatory transcription, which effectively prevents STAT3-mediated barrier disruption. Targeting the CDK9-RNAPII-STAT3 axis presents a therapeutic strategy and highlights the potential of transcriptional intervention for promoting mucosal healing in UC.
METHODS: The effects of the selective CDK9 inhibitor, LDC000067 (LDC), in dextran sulfate sodium (DSS)-induced colitis mice and lipopolysaccharide (LPS)-stimulated Caco-2 cells were investigated. Disease severity, barrier ultrastructure, and molecular signaling pathways were assessed via histology, transmission electron microscopy (TEM), nuclear-cytoplasmic fractionation, and immunofluorescence.
RESULTS: LDC administration significantly ameliorated clinical symptoms, preserved colonic length, and mitigated histological injury in DSS-induced mice. Crucially, it protected epithelial ultrastructure and replenished mucin-secreting goblet cells. Mechanistically, CDK9 inhibition suppressed the inflammatory cytokine secretion (particularly IL-6) and inhibited RNAPII Ser2 phosphorylation, thereby attenuating the availability of upstream IL-6, which in turn correlated with reduced phosphorylation and nuclear translocation of STAT3. In vitro experiments corroborated that LDC impeded LPS-induced STAT3 nuclear translocation, consequently rescuing tight junction protein expression (ZO-1, Occludin) and reinforcing transepithelial electrical resistance (TEER).
CONCLUSION: Collectively, LDC alleviates colitis by broadly dampening inflammatory transcription, which effectively prevents STAT3-mediated barrier disruption. Targeting the CDK9-RNAPII-STAT3 axis presents a therapeutic strategy and highlights the potential of transcriptional intervention for promoting mucosal healing in UC.