Physcion alleviates ulcerative colitis by upregulating SIRT3 to suppress PANoptosis via inhibition of the cGAS-STING pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhubarb (Rheum rhaponticum L.), a traditional Chinese herb, boasts a long-standing tradition of use in alleviating gastrointestinal ailments. Physcion (PHY), a major bioactive anthraquinone derived from rhubarb, possesses anti-inflammatory as well as antioxidant properties, suggesting therapeutic potential for ulcerative colitis (UC).

AIM OF THE STUDY: This study sought to explore PHY's protective role against UC and elucidate its underlying molecular mechanisms.

MATERIALS AND METHODS: A murine UC model was established using dextran sulfate sodium (DSS). PHY or 5-ASA were orally administered to treated groups. Intestinal epithelial cells (IECs) were challenged with LPS and co-treated with PHY. Key assessments included disease activity, intestinal barrier integrity, inflammation, oxidative stress, and programmed cell death. SIRT3 knockdown and Co-IP assays were performed to confirm PHY's role.

RESULTS: PHY administration mitigated DSS-triggered UC, evident from diminished disease severity, maintained colon length, and enhanced histopathology. PHY bolstered intestinal barrier integrity by boosting tight junction proteins and ameliorated oxidative stress and inflammation. Mechanistically, PHY inhibited the integrated PANoptosis (a multifaceted programmed cell death) in vivo and in vitro. Furthermore, it upregulated SIRT3 expression and subsequently inhibited the cGAS-STING signaling pathway. SIRT3 knockdown abolished the protective effects of PHY on barrier genes, inflammatory signaling, and PANoptosis suppression. Co-IP analysis confirmed that PHY modulated the interaction between SIRT3 and cGAS.

CONCLUSIONS: PHY exerts a protective effect against UC by strengthening the intestinal barrier, reducing inflammation, and inhibiting PANoptosis. This therapeutic efficacy is mediated through SIRT3 upregulation and subsequent downregulation of the cGAS-STING pathway.