Abstract: Objective To investigate the protective effects of caspase-1 inhibitor VX765 on gastric mucosa of mice with cold-restraint stress-induced acute gastric ulcer. Methods Twenty-four specific pathogen free male C57BL/6J mice were divided into normal control group (NC), cold restrain group (CR), VX765 pre-treatment+ cold restrain group (VCR), and rabeprazole pre-treatment+ cold restrain group (RCR) according to the random number table, with 6 mice in each group. Mice in group NC were injected intraperitoneally with solution of 10 mL/kg dimethylsulfoxide (DMSO) and phosphate buffer solution (PBS). Mice in group CR were inflicted with acute gastric ulcer induced by cold-restraint stress 30 minutes after intraperitoneal injection of solution of DMSO and PBS. Mice in groups VCR and RCR were inflicted with acute gastric ulcer as above 30 minutes after intraperitoneal injection of solution of DMSO and PBS with dose of 12.5 μmol/kg containing 10 mg VX765 and 40 mg/kg containing 20 mg rabeprazole, respectively. Four hour after cold-restraint stress, serum content of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6)was determined by enzyme-linked immunosorbent assay. Gross condition of gastric tissue was observed. Ulcer index was evaluated. Pathological change of gastric tissue was observed with HE staining. The relative expression of IL-1β, IL-18, and cleaved-caspase-1 in gastric tissue were detected by Western blotting. Mice in group NC were detected as above at the same time point. Data were processed with one-way analysis of variance and Bonferroni test. Results The serum content of TNF-α and IL-6 and the relative expression of cleaved-caspase-1, IL-1β, and IL-18 in gastric tissue of mice in group NC were significantly lower than those in group CR (with P values below 0.01). The content of the above-mentioned inflammatory indexes in serum and gastric tissue of mice in group VCR was significantly lower than that in group CR (with P values below 0.01). There were no statistically significant differences in content of the above-mentioned inflammatory indexes in serum and gastric tissue of mice between groups RCR and CR (with P values above 0.05). The content of the above-mentioned inflammatory indexes in serum and gastric tissue of mice in group VCR was significantly lower than that in group RCR (with P values below 0.01). Surface of gastric mucosa was smooth and morphology of mucosal cells was normal with clear structure of mice in group NC. Multiple hemorrhage of gastric mucosa, disorderly arrangement of mucosal cells, and large number of inflammatory cell infiltration around necrotic tissue were observed in mice of group CR. Decreased number of gastric mucosa bleeding, intact mucosal structure, and small amount of inflammatory cell infiltration around necrotic tissue were observed in mice of groups VCR and RCR. The ulcer indexes of mice in groups NC, CR, VCR, and RCR were 0, 18.7±1.1, 6.3±1.5, and 8.2±1.3, respectively. The ulcer index of mice in group NC was significantly lower than that in the other 3 groups (with P values below 0.05). The ulcer indexes of mice in groups VCR and RCR were close (P>0.05), which were significantly lower than ulcer index of mice in group CR (with P values below 0.05). Conclusions VX765 can effectively inhibit the activation of caspase-1, reduce production of inflammatory factor, and alleviate inflammatory response, which have protective effects on gastric mucosa of mice with cold-restraint stress-induced acute gastric ulcer.