Ginsenoside compound K restrains hepatic fibrotic response by dual-inhibition of GLS1 and LDHA.

Background: Liver fibrosis is a dynamic process marked by the accumulation of extracellular matrix due to hepatic stellate cells (HSCs) activation. Ginsenoside compound K (CK), a rare derivative of its parent ginsenosides, is known to significantly ameliorate metabolic disorders.

Purpose: The aim of this study was to elucidate the protective effects of CK against liver fibrosis with a focus on metabolic regulation.

Methods: We established liver fibrosis models in mice using carbon tetrachloride (CCl₄) challenge, bile duct ligation, or a methionine-choline deficient diet, with continuous oral administration of CK at specified doses and intervals. Simultaneously, we examined the impact of CK on metabolic regulation in cultured HSCs and investigated the associated mechanisms.

Results: CK was found to alleviate liver injury and curb fibrotic responses in mouse models, as well as decrease elevated levels of liver enzyme. Metabolomic analysis in vitro highlighted the crucial roles of pyruvate and glutamine metabolism in metabolic remodeling. Immunohistochemical staining indicated significantly elevated expressions of lactate dehydrogenase A (LDHA) (p = 0.014) and glutaminase 1 (GLS1) (p = 0.024) in liver cirrhosis patients. Comparable alterations were noted in the liver of model mice and in cultured HSCs. Molecular docking and bio-layer interferometry demonstrated that CK interacts with and inhibits the activities of LDHA and GLS1. As expected, CK attenuated glycolysis and glutaminolysis, reducing HSC growth dependently on lactate and α-ketoglutarate (α-KG). Upon HSC activation, metabolism is reprogrammed with Myc as a key regulator, transcriptionally controlling LDHA, GLS1, and glutamine transporters SLC1A5 and SLC38A5. CK inhibited Myc induction, integrating glycolysis and glutaminolysis regulation to counteract the fibrotic response.

Conclusion: CK inhibited LDHA and GLS1 activities, thereby inhibiting hepatic fibrosis. These findings offer new insights into the role of ginsenosides in liver protection, especially regarding metabolic disorders.