Inhibition of CDK9 improves colonic epithelial dysfunction in DSS-induced ulcerative colitis mice by blocking the...

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.

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.

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).

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.