Multi-target mechanisms of glabrone in ulcerative colitis: Synergistic restoration of mucosal barrier and inhibition of inflammation through SRC/HSP90 Co-modulation.

Abstract

OBJECTIVE: This study aimed to investigate the multi-target mechanisms of Glabrone, an isoflavonoid derived from licorice, in the treatment of ulcerative colitis (UC), focusing on its synergistic effects in mucosal barrier repair and inflammation suppression. METHODS: The therapeutic effects of Glabrone were assessed in 3 % DSS-induced UC mice model. Evaluations included disease severity, histopathological damage, inflammatory cytokine levels, and intestinal barrier integrity. The anti-inflammatory activity of Glabrone was further examined in LPS-stimulated NCM460 and RAW264.7 cells. Potential targets were predicted using network pharmacology and molecular docking and subsequently validated through experimental approaches. Preliminary in vivo safety was also evaluated. RESULTS: Glabrone administration significantly alleviated UC symptoms, as indicated by reduced disease activity index, restored colon length, and improved histopathological changes. It demonstrated synergistic therapeutic effects by enhancing the mucosal barrier through upregulation of tight junction proteins (ZO-1, Occludin-1, and Claudin-1) and increased goblet cells, while simultaneously suppressing inflammation via reduction of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β). Furthermore, Glabrone was found to target SRC and HSP90, inhibit PI3K-Akt pathway, and activate p53 and estrogen receptor signaling pathways. Critically, Glabrone effectively antagonized SRC activation induced by MSI-1436, providing evidence for SRC as a key therapeutic target. This co-modulation of SRC/HSP90 underpins its multi-target action. Importantly, Glabrone showed no significant toxicity in vivo. CONCLUSION: Glabrone ameliorates UC through coordinated modulation of SRC/HSP90, which synergistically promotes mucosal barrier restoration and suppresses inflammatory responses. These results provide theoretical basis for developing Glabrone as a candidate multi-target therapeutic agent for UC.