Hernandezine alleviates inflammatory bowel disease by enhancing gut barrier integrity via the AMPK/NRF2 pathway and regulating immune-metabolic balance.

Inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, is characterized by chronic inflammation and impaired intestinal barrier function. Current therapeutic approaches primarily aim to suppress the overly active immune response using aminosalicylates and immunosuppressive agents, which are frequently associated with significant adverse effects. In this study, we evaluated the therapeutic potential and underlying mechanisms of Hernandezine (HER), a bioactive compound extracted from Thalictrum, using a dextran sulfate sodium (DSS)-induced murine colitis model. We found that HER treatment significantly alleviated DSS-induced colitis symptoms, histological damage, and intestinal barrier disruption. Mechanistically, HER enhanced intestinal epithelial barrier integrity by activating the AMPK/NRF2 signaling pathway, leading to increased NRF2 nuclear translocation and improved expression of tight junction proteins. Additionally, HER modulated intestinal immune homeostasis by reducing inflammatory cytokine production and maintaining Th17/Treg balance. Moreover, HER alters intestinal metabolite profiles by diminishing pro-inflammatory compounds and promoting beneficial metabolites linked to reduced inflammation, ultimately enhancing intestinal epithelial protection. Collectively, our findings indicate that HER exerts potent protective effects against experimental colitis through coordinated immunomodulatory, barrier-enhancing, and metabolic regulatory actions, positioning it as a promising new therapeutic option for managing IBD.