PSME2 exacerbates ulcerative colitis by disrupting intestinal barrier function and promoting autophagy-dependent inflammation.

The immunoproteasome regulatory component proteasome activator subunit beta (PSME2) plays a crucial role in immune regulation, yet its impact on intestinal barrier integrity in ulcerative colitis (UC) remains unclear. This study aimed to elucidate the involvement of PSME2 in UC pathogenesis. Clinical samples from UC patients and healthy controls were analyzed to assess PSME2 expression. A dextran sulfate sodium-induced colitis mouse model was employed to evaluate disease progression, colon histology, and PSME2 levels. In vitro, colonic cells were treated with lipopolysaccharide (LPS) to examine tight junction protein (claudin-1) expression and inflammatory mediators (IL-6, IL-10, TNF-α). Autophagy modulation was investigated using PSME2 silencing and chloroquine (CQ) treatment. PSME2 upregulation in UC and colitis mice correlated with disease severity. In vitro, LPS suppressed claudin-1 expression, while PSME2 knockdown restored claudin-1 levels and reduced inflammatory cytokines. PSME2 depletion enhanced autophagy, as indicated by an increased LC3-II/LC3-I ratio, reduced p62, and elevated LC3B puncta. CQ treatment reversed the protective effects of PSME2 silencing, confirming autophagy's role in barrier integrity. PSME2 exacerbates intestinal inflammation by promoting cytokine release and disrupting epithelial barrier function through autophagy dysregulation. Suggesting its potential as a therapeutic target.