Tanshinone IIA alleviates ferroptosis and oxidative injury in chronic experimental colitis through Nrf2 activation.

Abstract

This study aims to explore the mechanism by which Tanshinone IIA (Tan IIA) inhibits ferroptosis and oxidative injury in TNBS-induced Inflammatory Bowel Disease (IBD) in mice. Experimental colitis was induced by the rectal administration of 2,4,6-Trinitrobenzenesulfonic acid (TNBS). Primary intestinal cells, luciferase reporter assay and nuclear factor erythroid 2-related factor 2(Nrf2)-null mice were used to clarify if Tan IIA ameliorates ferroptosis and oxidative injury in TNBS-induced colitis dependent on Nrf2. Tan IIA (20 mg/kg) ameliorated colonic weight/length ratio, pathological scores and fibrosis in TNBS-induced mice. Moreover, Tan IIA reduced pro-inflammatory factors and increased the expression of tight junction proteins, likely contributing to the improvement of colonic barrier integrity. Tan IIA significantly induced the expression of Nrf2 target genes in primary intestinal epithelial cells and activated Nrf2 luciferase reporter activities in HCT116 cells. In TNBS-induced wild-type mice but not in Nrf2-null mice, Tan IIA significantly improved ferroptosis and oxidative injury as revealed by decreased ferritin light chain (FTL) level and upregulated Nrf2 downstream genes heme oxygenase-1 (HO-1) and superoxide dismutase 1 (SOD1) expression. In conclusion, Tan IIA significantly alleviates colonic ferroptosis and oxidative injury induced by TNBS in mice through modulation of the Nrf2 signaling.