Ginsenoside Rg1 exerts antidepressant effect by regulating hepatic kynurenine metabolism through promoting the interaction between HNF4α and PGC1α.

Background: The neuroprotective effect of ginsenoside Rg1 is indeed one of the current research hotspots. However, its limited ability to cross the blood-brain barrier results in low distribution within the brain. Thus, the mechanism through which ginsenoside Rg1 affects the central nervous system needs further examination. Methods: The LC-MS/MS analysis was used to detect the Kyn level. The expression of kynurenine aminotransferase 2 (KAT2) and kynurenine 3-monooxygenase (KMO) were investigated by qRT-PCR and western blotting analysis. The interaction between the transcription factor hepatocyte nuclear factor-4α (HNF4α) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) was explored by Co-IP assay. The HNF4α binding sites in the KAT2 and KMO genes were analyzed by ChIP. In addition, we specifically knocked down HNF4α in the liver of mice by injecting adeno-associated virus into the tail vein. Results: Ginsenoside Rg1 upregulated the expression of KAT2 and KMO, thereby increasing the metabolism of Kyn in the liver. Further exploring its mechanism, we discovered that ginsenoside Rg1 increased the expression of KAT2 and KMO by promoting the interaction between the transcription factor HNF4α and PGC1α. Hepatic HNF4α knockdown abolished the antidepressant effects induced by ginsenoside Rg1. Conclusion: Our findings reveal a novel mechanism in which ginsenoside Rg1 upregulates KAT2 and KMO through the HNF4α/PGC1α pathway, reducing hepatic Kyn levels and subsequently alleviating depression.