Tanshinone IIA Inhibits Experimental Colitis by Activating PregnaneX Receptor to Suppress the Interleukin-6/Signal Transducer and Activatorof Transcription 3 Pathway

Objective: Tanshinone IIA (TanIIA), isolated from the traditional herbal medicine Salvia miltiorrhiza Bunge, was reported to inhibit Inflammatory Bowel Disease (IBD). Considering that the Pregnane X Receptor (PXR) is known to influence IBD, we sought to elucidate the potential underlying mechanisms of TanIIA’s anti-colitis effects by investigating the impact of TanIIA on the PXR signaling pathway. Methods: Wild-type and Pxr-null mice were treated with TanIIA or vehicle and given 2.5% Dextran Sulfate Sodium (DSS) in drinking water to induce colitis. Primary intestinal epithelial cells were used in vitro to assess the effect of TanIIA on PXR expression and its target genes. Immunohistochemical analysis was performed to examine PXR expression in colonic mucosal biopsy samples from the healthy controls and patients with Crohn's Disease (CD). Results: On day 7, TanIIA increased DSS-induced body weight by 7.67 %, restored colon length by 13.98 % (both p < 0.01), and ameliorated histopathological damage in WT mice; no protection was observed in Pxrnull mice. TanIIA significantly induced the expression of the PXR target gene Cyp3a11 (p < 0.01) in primary intestinal epithelial cells and DSS-induced wild-type mice. PXR expression was significantly reduced (p < 0.001) in CD patients compared with healthy controls and was negatively correlated with pathological scores (r = -0.8, p < 0.001). Mechanistically, TanIIA inhibited IL-6 secretion and STAT3 activation (p < 0.01) in a PXR-dependent manner. Discussion: This study revealed that TanIIA exerts its anti-colitis effect primarily through activating PXR and inhibiting the IL-6/STAT3 inflammatory pathway, which represents its key mechanism of action. The downregulation of PXR expression in the colonic tissues of patients with Crohn's disease, which is negatively correlated with disease severity, further supports the importance of PXR as a therapeutic target for IBD. The experimental results provide crucial evidence for its clinical application and the development of PXRtargeted drugs. Conclusion: TanIIA demonstrated significant efficacy against IBD by activating the nuclear receptor PXR and inhibiting the IL-6/STAT3 signaling pathway.