Dehydrocostus lactone attenuates ulcerative colitis via USP38-mediated histone H2B Deubiquitination to suppress NF-κB-driven inflammation.

Ulcerative colitis (UC) is a major form of inflammatory bowel disease (IBD). Dehydrocostus lactone (DHL), the primary medicinal component of Aucklandia lappa DC (Mu Xiang), exhibits diverse pharmacological effects. However, the precise mechanism underlying its anti-UC activity remains unclear. This study investigated the protective effects of DHL against Dextran Sulfate Sodium (DSS)-induced colitis in mice and elucidated the underlying molecular mechanisms, using Hematoxylin-Eosin staining, Western Blot (WB), immunofluorescence staining, and ELISA assays. Treatment with DHL significantly reduced the weight loss, macroscopic scores, and colonic pathological degeneration in mice with colitis. Additionally, DHL promoted M2 macrophage polarization and suppressed the inflammatory response. Mechanistically, DHL increased the expression of ubiquitin-specific peptidase 38 (USP38) and decreased the elevated histone H2B ubiquitination (H2Bub) levels, while concurrently inhibiting nuclear factor-kappa B p65 subunit (p65) binding to the interleukin-6 (IL-6) and interleukin-23α (IL-23α) promoters. In summary, our findings demonstrated that DHL could activate USP38, which in turn induces the deubiquitination of histone H2B and reduces the level of H2B ubiquitination (H2Bub). This subsequently inhibited the recruitment of nuclear factor kappa-B (NF-κB) to the promoter regions of IL-6 and IL-23α, thereby alleviating intestinal inflammatory responses in UC.