Shaoyao Gancao Decoction alleviates ulcerative colitis-associated secondary liver injury by inhibiting the phosphorylation of pyruvate dehydrogenase in macrophages.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: The classic formula Shaoyao Gancao Decoction (SGD) originates from "Treatise on Exogenous Febrile Disease". Traditionally, it is used to treat ulcerative colitis (UC) and the secondary liver injury. However, its mechanism is still unclear. AIM OF THE STUDY: To evaluate the efficacy of SGD on the secondary liver injury in UC and explore its potential mechanisms. MATERIALS AND METHODS: A mouse model of UC with liver injury was established using dextran sulfate sodium. Therapeutic effects were assessed via histopathology and serum biochemistry. Mechanisms were explored through RNA sequencing, quantitative metabolomics, molecular docking, and confirmatory experiments. RESULTS: SGD alleviated histopathological damage in the colon and liver, and reduced serum ALT/AST levels. RNA sequencing indicated that glycometabolism signaling was shifted in the liver tissues of the model mice, while SGD treatment mitigated this change. Additionally, the M1 polarization of macrophages is inhibited by SGD. Quantitative metabolomics revealed that SGD upregulated the flux of the tricarboxylic acid cycle in lipopolysaccharide-stimulated macrophages. The components within SGD could bind to PDH and PDK respectively, thereby blocking the PDK-PDH interaction, thus prevent the phosphorylation of PDH. The intervention of the PDH inhibitor weakened the inhibitory effect of SGD on macrophage polarization. Molecular docking experiments indicated that benzoylpaeoniflorin and glycyrrhizic acid bind to PDH and PDK, respectively. CONCLUSIONS: These findings elucidate that SGD improves the secondary liver injury in UC by blocking PDK-PDH binding, thereby inhibiting M1 polarization of macrophages.