AIM:To explore the molecular mechanism of Tiaopi Chengqi decoction (TpCqD) improving hyperthermia and high-protein food-induced hyperphagia mice based on transcriptomics. METHODS:C57 mice were randomly divided into a control group, model group, low-dose TpCqD group, high-dose TpCqD group, and domperidone group. The general condition of the experimental mice was observed and the average food intake was counted, and the rate of gastric emptying and intestinal propulsion was determined for each group of mice. H&E staining was used to observe pathological changes in gastric tissue. PAS staining was used to observe glycogen changes in gastric tissue. Pepsin activity was determined by colorimetry. pH value of gastric contents was measured by acid-base titration. Transcriptome sequencing was used to analyze the differential genes in gastric tissue, a volcano map and a cluster heat map were made for the differential genes, and KEGG was used to analyze the signal pathway enrichment of the differential genes. RT-qPCR verified the differential genes obtained by screening. RESULTS:After treatment with TpCqD, the body weight and average food intake of mice with food accumulation increased (P<0.05), and the intestinal propulsion rate and gastric emptying speed of mice with food accumulation accelerated (P<0.05). TpCqD could protect gastric tissue structure and glycogen degradation, increase pepsin activity (P<0.05), and reduce gastric content pH (P<0.05). Transcriptome results showed that TpCqD could regulate the expression of Acox2 and cilp2, regulate fat digestion and absorption, protein digestion and absorption, and pancreatic secretion signals. RT-qPCR showed that compare with model group, TpCqD up-regulated Acox2 (P<0.05) and down-regulated the mRNA level of cilp2 (P<0.05). CONCLUSION:TpCqD ameliorated digestive dysfunction in mice with high-calorie and high-protein diets leading to food accumulation involving the regulation of the fat and sugar metabolism genes Acox2 and cilp2, and pancreatic secretory signaling.