Activating PXR by Curcumol Ameliorates DSS-Induced Ulcerative Colitis via Transcriptional Repression of STING Signaling

Pregnane X receptor (PXR) deficiency is implicated in ulcerative colitis (UC) pathogenesis, although its mechanistic role remains incompletely defined. Curcumol (CUR), a natural compound derived from the medicinal and culinary plant <i>Curcuma longa L.</i>, possesses broad pharmacological activities (e.g., anti-inflammatory, antifibrotic, anticancer) as reported in the literature. However, its therapeutic potential for UC remains unreported. This study aimed to investigate whether CUR has pharmacological activity that improves UC in mice and its mechanism of action. Through our research, we demonstrated that CUR ameliorates DSS-induced UC in mice by reducing intestinal inflammation and restoring barrier integrity. Transcriptomic and <i>in vitro</i> analyses revealed that CUR activates the murine PXR (mPXR) pathway, with mPXR deficiency abolishing its therapeutic effects. Further profiling showed that CUR directly suppresses DNA damage signaling, prominently inhibiting the STING pathway. ChIP assays confirmed that human PXR (hPXR), acting as a ligand-dependent transcription factor, binds and represses the STING promoter. Critically, blocking STING attenuated exacerbated UC pathology in mPXR-deficient mice, while STING activation reduced CUR's anti-UC efficacy. CUR-mediated activation of colonic mPXR contributes to the attenuation of DSS-induced colitis-associated phenotypes by transcriptionally repressing colonic STING expression. Our results demonstrate that CUR serves as a promising lead compound for the treatment of UC.