Isoliquiritigenin alleviates ethanol-induced gastric ulcers by modulating the TNF signaling pathway and targeting IL-6

Alcoholic gastric ulcer is a clinically prevalent gastrointestinal disorder whose pathogenesis is closely associated with both the direct mucosal damage induced by ethanol and the subsequent inflammatory response. Isoliquiritigenin (ISL), a major bioactive flavonoid from Glycyrrhiza, exhibits anti-inflammatory and antioxidant properties. This study investigated ISL's protective effects and mechanisms against ethanol-induced gastric ulcers (GU). Results showed ISL significantly alleviated GU in rats and gastric epithelial cells. Transcriptomic analysis identified 470 differentially expressed genes reversed by ISL, enriched in inflammatory response and TNF signaling. RT-qPCR validated these findings. Western blot confirmed ISL inhibited key proteins in the TNF pathway. Protein-protein interaction (PPI) network analysis highlighted IL-6 as a central hub protein occupying a pivotal position within the network architecture. Molecular docking, dynamics simulations, and bio-layer interferometry demonstrated strong binding between ISL and IL-6. In summary, ISL exhibits a protective effect against ethanol-induced GU. The potential mechanism may involve the TNF pathway, through which it exerts modulatory effects on this pivotal inflammatory signaling axis, leading to reduced apoptosis and gastric mucosal injury. This study identifies ISL, a constituent derived from food, as a novel adjuvant therapeutic agent for GU, supporting its use in clinical management.