〔Abstract〕 Objective To investigate the effects of forkhead box protein O4（FOXO4）expression on gastric pre⁃ cancerous lesions（GPL），and to clarify its mechanism in mediating the therapeutic effect of Celastrus orbiculatus extract（COE）on GPL by regulating aerobic glycolysis. Methods Referring to the previously established com ⁃ bined modeling protocol in our research group，a rat model of gastric precancerous lesions（GPL）was constructed through the following procedures：rats were given free access to 170 μg/mL N-methyl-N ′-nitro-N-nitrosoguanidine （MNNG）solution for ad libitum drinking，fed with a diet supplemented with 0. 03% ranitidine hydrochloride，and treated with a cycling regimen of“2-day feeding followed by 1-day fasting ”. Specifically，on the afternoon of each fasting day，the rats received intragastric administration of 2% sodium salicylate at a dose of 10 mL/kg body weight. FOXO4-silenced and overexpression model rats were constructed by tail vein injection of plasmids. The rats were randomly divided into control，model，COE，overexpression negative control（OE-NC），FOXO4 overex⁃ pression（OE-FOXO4）， OE-FOXO4+COE，silencing negative control（shNC）， FOXO4 silencing（shFOXO4） and shFOXO4+COE groups. Gastric mucosal histopathological changes were observed in each group. Lactic acid content in gastric mucosal tissues was detected by colorimetry. The expression levels of FOXO4，HK2，PKM2， LDHA and GLUT 1 were evaluated by immunohistochemistry（IHC）， and their mRNA levels were determined by RT-PCR. Results Compared with the control group，the COE，OE-FOXO4 and OE-FOXO4+COE groups exhib_ ited significantly improved gastric mucosal lesions，reduced lactic acid levels，weakened expression of aerobic glycolysis-related proteins（PKM2，HK2，LDHA，GLUT 1），and enhanced FOXO4 expression. The OE-FOXO4+ COE group showed the lowest lactic acid level and more pronounced changes in related protein expression com_ pared with the COE and OE-FOXO4 groups. In contrast，the shFOXO4 and shFOXO4+COE groups displayed in_ creased lactic acid levels，enhanced expression of aerobic glycolysis-related proteins，and reduced FOXO4 expres_ sion compared with the model group. Conclusion FOXO4 expression is involved in the inhibitory effect of COE on GPL，possibly by regulating the aerobic glycolysis process.