Pretreatment with Citrus reticulata ‘Chachi’ Polysaccharide Alleviates Alcohol-Induced Gastric Ulcer by Inhibiting NLRP3/ASC/Caspase-1 and Nrf2/HO-1 Signaling Pathways

Objectives: This study was designed to investigate the gastroprotective effects of Citrus reticulata ‘Chachi’ polysaccharide (CRP) against alcohol-induced gastric ulcers (GUs) and to elucidate its underlying mechanisms. Methods: CRP was extracted, purified, and structurally characterized. BALB/c mice (50/250 mg/kg CRP) and GES-1 cells (1 mg/mL CRP) were subjected to alcohol-induced injury. Oxidative stress (SOD, MDA, ROS), inflammation (TNF-α, IL-1β, NLRP3 inflammasome), mucosal barrier proteins (ZO-1, occludin, Claudin-5), and Nrf2/HO-1 signaling were analyzed via histopathology, Western blot, flow cytometry, and immunohistochemistry. Results: CRP pretreatment significantly alleviated gastric lesions, decreased oxidative stress, and suppressed inflammatory responses in alcohol-induced mice. Mechanistically, CRP induced the Nrf2/HO-1 antioxidant pathway while inhibiting the activation of the NLRP3 inflammasome. CRP also restored tight junction protein expression, enhanced mucosal repair, and reduced epithelial apoptosis. In vitro, CRP promoted cell proliferation, migration, and survival of GES-1 cells under alcohol stress. Conclusions: CRP mitigated alcohol-induced GU via dual antioxidant, anti-inflammatory, and barrier-protective mechanisms, positioning it as a considerable agent for GU.