Isoliquiritigenin suppresses ER stress-driven epithelial apoptosis to preserve barrier integrity in colitis

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by epithelial barrier disruption and chronic mucosal inflammation, and its underlying mechanisms remain incompletely understood. Increasing evidence suggests that endoplasmic reticulum (ER) stress contributes to epithelial injury and apoptosis and plays an important role in the development of UC. Isoliquiritigenin (ISL), a natural flavonoid derived from licorice, has been reported to exert anti-inflammatory and antioxidant effects. However, whether ISL alleviates UC by regulating ER stress-associated apoptosis and the underlying mechanisms remain unclear. This study aimed to determine whether ISL alleviates dextran sulfate sodium (DSS)-induced colitis by regulating ER stress-associated apoptosis and to explore the underlying molecular mechanisms. A DSS-induced colitis model was established in mice, and ER stress was induced in Caco-2 cells using tunicamycin. Disease severity was evaluated by disease activity index scoring, histological examination, mucus production assessment, and intestinal permeability analysis, and inflammatory cytokine levels were measured. Quantitative proteomics was performed to identify altered pathways. ER stress signaling and apoptosis-related proteins were further examined. In addition, the ER stress inhibitor 4-phenylbutyric acid (4-PBA) was used to verify the involvement of ER stress. The results showed that ISL markedly alleviated DSS-induced colitis, as evidenced by improved epithelial structure, mucus production, and barrier function, along with reduced levels of IL-6, IL-1β, TNF-α, and IL-17 A. Proteomic analysis revealed enrichment of ER protein processing and apoptosis-related pathways in DSS-treated tissues, which were partially reversed by ISL. DSS induced ER stress, as indicated by increased GRP78 (BiP) expression and activation of the PERK-eIF2α-ATF4-CHOP pathway, and promoted epithelial apoptosis, evidenced by Bax upregulation, caspase-3 activation, Bcl-2 reduction, and increased TUNEL-positive cells. ISL inhibited activation of this pathway and restored apoptotic balance. Consistently, ISL suppressed tunicamycin-induced ER stress, barrier dysfunction, and apoptosis in Caco-2 cells, whereas pharmacological inhibition of ER stress with 4-PBA produced similar protective effects. Collectively, these findings suggest that ISL attenuates DSS-induced colitis by inhibiting ER stress-mediated epithelial apoptosis, potentially through modulation of the PERK signaling pathway, thereby providing experimental evidence for its therapeutic potential in UC.