Trichostatin A ameliorates ulcerative colitis via the SERPINB5-mediated MMP9/RLN2 signaling pathway

To identify the key molecular target and elucidate the underlying mechanism by which the histone deacetylase inhibitor trichostatin A (TSA) treats ulcerative colitis (UC).

Murine UC models were established via chronic cyclic dextran sulfate sodium (DSS) administration (2.5% DSS for 5 days, followed by 14 days of recovery; repeated for 3 rounds), alongside Caco-2 cell injury models. Histological scoring, molecular biology techniques (Western blot, qPCR, co-immunoprecipitation), cellular functional assays (cell viability, inflammatory cytokines, oxidative stress, apoptosis, intestinal barrier integrity), bioinformatics analysis, and molecular docking were employed to dissect TSA's mechanisms both in vivo and in vitro. SERPINB5-Knockdown mice and SERPINB5-knockdown cell lines were further used to validate the critical role of this target.

TSA significantly ameliorated DSS-induced colonic shortening, histopathological damage, release of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-17, CRP), and oxidative stress (elevated ROS; reduced SOD/GSH-Px activity). It also suppressed intestinal epithelial cell apoptosis and restored expression of tight junction proteins (ZO-1, Occludin, E-cadherin), thereby improving intestinal barrier function. Mechanistically, TSA markedly downregulated SERPINB5 expression and reduced its protein stability. SERPINB5 was found to directly bind MMP9 and stabilize it by shielding it from ubiquitin-proteasome-mediated degradation, thereby sustaining MMP9 protein levels, promoting MMP9 activity, and suppressing the protective factor RLN2. Genetic ablation of SERPINB5 or pharmacological inhibition of MMP9 recapitulated the therapeutic effects of TSA, whereas MMP9 overexpression or RLN2 silencing partially reversed TSA-mediated protection in Caco-2 cells.

TSA improves ulcerative colitis by targeting the SERPINB5-MMP9-RLN2 signaling axis, thereby suppressing inflammation, oxidative stress, and apoptosis while preserving intestinal barrier integrity.