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ETHNOPHARMACOLOGICAL RELEVANCE "Xiaoerhuashi Pill, XP", with a history of 30 years in China, was included in the first part of the 2015 edition of the Chinese Pharmacopoeia and is widely used in the treatment for pediatric diseases in clinical application. Its main indications include the accumulation of heat caused by food stagnation in children, which has the effect of digestive stagnation and purge heat to relax the bowels. AIM OF THE STUDY High-calorie diet, closely related to the occurrence and development of multiple diseases, is an unhealthy status of life. However, there is no effective intervention in clinic. Thus, based on animal experiments and bioinformatics, this study aims to explore the potential mechanisms of action of Chinese patent medicine- "Xiaoerhuashi Pill, XP" in the intervention of high-calorie diet. MATERIALS AND METHODS A high-calorie diet model was prepared by 3-week-old rats. The defecation and intestinal mucosal morphology were observed after intragastric administration of "Xiaoerhuashi Pill, XP". The components of "Xiaoerhuashi Pill, XP" were obtained by chromatography-mass spectrometry, with the corresponding targets obtained by database and target fishing. The key effects substances were obtained by molecular docking, with the obtaining of the ore pathway of "Xiaoerhuashi Pill, XP" in intervention of high-calorie diet based on the enrichment analysis. RESULTS "Xiaoerhuashi Pill, XP" can actively interfere with defecation and intestinal mucosal structures in high-calorie diet animals. A total of 37 substances were identified in the pediatric digestion solution, and 356 target proteins were mapped, 25 of which were associated with a high-calorie diet. Overall, the analysis shows that the highest degree of integration was quercetin and PON1 protein, with the highest enrichment of insulin resistance pathway. CONCLUSION "Xiaoerhuashi Pill, XP" can intervene in the health status of high-calorie diet animals. Integration of quercetin and PON1 protein can regulate lipid levels, which may be the key mechanisms of action in "Xiaoerhuashi Pill, XP". The mechanisms, more specifically, may be related to the regulation of pancreas islet function, thus providing a reference for the clinical application of "Xiaoerhuashi Pill, XP", clinical intervention of high-calorie diet and new drug development.