ETHNOPHARMACOLOGICAL RELEVANCE: The dried fruit of Crataegus pinnatifida Bunge (Hawthorn in Chinese) is a traditional medicine used in China, Japan and Korea for thousands of years. Hawthorn is documented in the Chinese Pharmacopoeia, as a folk medicine that is used to eliminate food, strengthen the stomach, move qi and dissipate blood stasis, treat stagnation of meat and food, gastric distention and fullness, and has anti-inflammatory effects. Vitexin, a flavonoid glycoside, is an important biologically active compound derived from Hawthorn, with significant antioxidant and anti-inflammatory properties. The pharmacological effects of Hawthorn are highly correlated with the antioxidant and anti-inflammatory effects of vitexin. AIM OF THE STUDY: The aim of the present study was to investigate the effect of vitexin on the alleviation of chronic atrophic gastritis (CAG) induced by 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) in a rat model, as well as to elucidate the underlying mechanisms involved. MATERIALS AND METHODS: CAG was administered at a concentration of 170 μg/mL MNNG in the drinking water of rats, and the effects of vitexin (30 mg/kg, once daily for 6 weeks) on gastric tissues were subsequently analyzed. Pathological damage was assessed using H&E and AB-PAS staining. Gastrointestinal hormone levels, specifically motilin (MTL) and gastrin (GAS), were quantified using biochemical index determination kits. To evaluate the levels of cytokines, specifically IL-1β and IL-18, in gastric tissue, an enzyme-linked immunosorbent assay (ELISA) was performed. Additionally, to investigate the effects of vitexin on the NLRP3 inflammasome, GES-1 cells were subjected to treatment with lipopolysaccharide (LPS) and adenosine triphosphate (ATP). The targeting of NLRP3 by vitexin was assessed in vitro using CESTA, DARTS, and a synthesized biotin-labeled vitexin probe (biotin-vitexin) in conjunction with dual immunofluorescence. RT-PCR, Western blotting and immunofluorescence were used to evaluate the ameliorative effect of oysterin on LPS + ATP-induced GES-1 cells in vitro. RESULTS: Administration of vitexin significantly alleviated the symptoms of chronic atrophic gastritis (CAG) by reducing weight loss and minimizing gastric tissue damage. Treatment with vitexin in CAG rats effectively reduces the production of pro-inflammatory cytokines. Furthermore, vitexin attenuated the activation of the NLRP3 inflammasome in CAG induced by MNNG. Mechanistic experiments showed that NLRP3 is a direct cellular target of vitexin, while vitexin inhibited rat NLRP3 inflammasome. CONCLUSION: Vitexin mitigates MNNG-induced CAG, and its protective effect is linked to the inhibition of NLRP3 inflammasome activation.