Objective  To explore the molecular mechanism by which Guizhi Tang regulates liver lipid metabolism to characterize its pungent-warm effect, as well as provide new data support for the essence of the nature and efficacy of Guizhi Tang, and also lay an experimental foundation for its clinical rational and effective prevention and treatment of related diseases.

Methods  In the pharmacological study, 20 SPF mice were randomly divided into a control group and a Guizhi Tang group [9.84 g/(kg·d)], with 10 mice in each group. After 4 consecutive days of administration, the cold-heat tendency of mice was analyzed through behavioral experiments to evaluate the intervention effect of Guizhi Tang on the body's energy metabolism status and body temperature regulation. In a multi omics study, 6 SPF mice were randomly divided into a control group and a Guizhi Tang group, with 3 mice in each group. After administration,  UPLC-MS/MS technology was used to comprehensively detect lipid metabolites in mouse livers, screen differential metabolites, and identify metabolism-related pathways. Meanwhile, RNA was extracted from mouse liver tissues for transcriptome sequencing and library construction, followed by screening of differentially expressed genes and enrichment analysis. The STRING platform was used to construct a protein-protein interaction network to identify core targets and pathways. Combined analysis of transcriptome and lipidome data was performed to construct an interaction effect network, and clarify the key pathways and related targets involved in the regulation of lipid metabolism by Guizhi Tang.

Results The behavioral testing results showed that, from the first day to the fourth day after administration, mice in the Guizhi Tang group showed a significant tendency to move toward the low-temperature area (P<0.05). A total of 45 differential lipid metabolites were detected by lipidomics, and the core metabolites included triglycerides, phosphatidylcholines, diglycerides, the pathways included sphingolipid metabolism, glycerolipid metabolism, linoleic acid metabolism, ether lipid metabolism. Transcriptomics screening identified 62 significantly up-regulated genes and 52 down-regulated genes (P<0.05). Multi-omics combined analysis revealed that key genes such as Fmo3, CYP2g1, CYP2a22, Srebf1, Gal3st1, and Slc22a27 regulated 28 differential lipid metabolites.

Conclusion  Guizhi Tang can promote lipid metabolism by regulating specific genes and pathways (e.g., glycerophospholipid metabolism, linoleic acid metabolism), thereby enhancing the body's heat production capacity and heat output. This characterizes the overall "pungent-warm" medicinal property of Guizhi Tang and its main effects of inducing sweating to relieve exterior symptoms, warming the meridians, and activating yang. The results of this study not only provide new data support for the essence of the nature and efficacy of Guizhi Tang but also lay an experimental foundation for its prevention and treatment of energy metabolism-related diseases and inflammation-related diseases.

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