Exploring the mechanisms of Yinchenhao decoction against ANIT-induced cholestatic liver injury by lipidomics, metabolomics and network pharmacology

Abstract

Yinchenhao decoction (YCHD) has been used for the treatment of cholestasis for more than 1000 years with clear clinical efficacy. However, its active compounds and pharmacological mechanism against cholestasis are unclear. In this study, an integrated strategy of network pharmacology, lipidomics, metabolomics, and molecular docking were performed to elucidate the mechanism of YCHD’s anti-cholestasis effect. Network pharmacology demonstrated YCHD mainly modulated lipid and atherosclerosis signaling pathways with the involvement of NF-κB, TNF, MAPK, and PI3K/AKT signaling pathways. In vivo experiments, male C57BL/6 J mice model of cholestasis was established by alpha-naphthyl isothiocyanate (ANIT), and were treated with different dosages (3 g/kg and 9 g/kg) of YCHD for one week. Ursodeoxycholic acid (UDCA) was used as a positive control. The in vivo experiments verified the ameliorative effect of YCHD on inflammation, hepatocellular injury and cholestasis. Furthermore, lipidomics and metabolomics research showed that YCHD could improve the metabolism disorder of glycerolipid, glycerophospholipid and amino acids. Subsequently, further WB and molecular docking validation experiments showed that the active compounds in YCHD have regulatory effects on the PPARγ/NF-κB/JNK pathway, the core pathway in lipid and atherosclerosis pathways, thereby inhibiting inflammatory response and improving lipid metabolism disorders. This study could provide evidence of the molecular mechanism and material basis of YCHD in treating cholestasis. This study also provided new research ideas for the discovery of active ingredients in traditional Chinese medicine formulas for the treatment of cholestasis.