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Background: Yanghe decoction is a famous formula consisting of Rehmannia , deer horn gum, cinnamon, rue, Ephedra , ginger charcoal, and licorice. However, few studies have explored the role of the potential mechanism of Yanghe decoction in the treatment of Hashimoto's thyroiditis by metabolomics., Methods: Nine mice were randomly divided into three groups: control group (group C), model group (group M), and drug administration group (group T), with three mice in each group. Mice in groups M and T were established as models of Hashimoto's thyroiditis, and group T was treated with Yanghe decoction. The metabolome of plasma samples from each group of mice was determined using mass spectrometry coupled with high-performance liquid and gas phases, and nuclear magnetic resonance. Based on the three assays, principal component analysis was performed on all samples, as well as orthogonal partial least squares-discriminant analysis and differential metabolite molecules for groups M and T. Subsequently, pathway enrichment analysis was performed, and the intersection was taken for the differential metabolites screened in the M and T groups. The levels of inflammatory factors IL-35 and IL-6 within the serum of each group of mice were detected., Results: The difference analysis showed that a total of 38 differential metabolites were screened based on mass spectrometry coupled with the high-performance liquid phase, 120 differential metabolites were screened based on mass spectrometry coupled with gas phase, and a total of α -glucose and β -glucose were the differential metabolites analyzed based on NMR test results. The pathways enriched by the differential metabolites in the M and T groups were intersected, and a total of 5 common pathways were obtained (amino acid tRNA biosynthesis, D-glutamine and D-glutamate metabolism, tryptophan metabolism, nitrogen metabolism, and arginine and proline metabolism). The results also showed a significant decrease in the serum inflammatory factor IL-35 and a significant increase in IL-6 in mice from group M compared with group C, while a significant increase in the serum inflammatory factor IL-35 and a significant decrease in IL-6 in mice from group T compared with group M., Conclusion: Our study reveals the metabolites as well as a metabolic network that can be altered by Yanghe decoction treatment of Hashimoto's thyroiditis and shows that Yanghe decoction can effectively reduce the level of inflammatory factors in Hashimoto's thyroid., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Xing Zhang et al.)