Celastrol Alleviates Intestinal Epithelial Permeability by Inhibiting Ferroptosis through PI3K/Akt/FOXO1/HO-1 Signaling Pathway

Ulcerative colitis (UC) is a recurrent inflammatory intestinal disorder characterized by systemic inflammatory response, abnormal intestinal epithelial cell death, and damage to the intestinal mucosal barrier. This study aimed to explore the role of celastrol in ferroptosis and intestinal epithelial barrier permeability. The results demonstrated that celastrol significantly inhibited ferroptosis in RSL3-induced intestinal epithelial cells by regulating the expression of ferroptosis-related proteins. Concurrently, celastrol dramatically improved the permeability of the intestinal epithelial monolayer by increasing the expression of tight junction proteins including ZO-1, occludin, and claudin-1. Moreover, celastrol markedly attenuated the effect of RSL3 on the phosphorylation of Akt and FOXO1. LY294002, a PI3K inhibitor, significantly inhibited the role of celastrol in the expression of ferroptosis-related and intestinal tight junction proteins. <i>In vivo</i>, celastrol administration not only significantly ameliorated dextran sulfate sodium (DSS)-induced colitis by preventing neutrophil infiltration, but also ameliorated intestinal mucosa damage, and colon shortening. Celastrol administration was also found to reduce the expression of ferroptosis-related proteins prevent the infiltration of fluorescein isothiocyanate-dextran (FITC-dextran) and increase the levels of tight junction proteins. Collectively, these findings suggest that due to its effects on ferroptosis and tight junctions in intestinal epithelial cells, celastrol may be a compound with significant promise in the prevention and treatment of UC.