Comprehensive multi-omics analysis revealed the mechanism of Panax ginseng extract in alleviating Qi deficiency liver cancer

Qi deficiency liver cancer (QDLC) accounts for a high proportion of liver cancer patients and is an important aspect of traditional Chinese medicine research on liver cancer. Panax ginseng (PG) known as the king of herbs, has significant advantages in QDLC due to its unique Qi-replenishing properties. However, its potential pharmacodynamic components and mechanisms on QDLC are not fully understood. This study aimed to elucidate the mechanism by which PG alleviates QDLC. A QDLC rat model was established using exhaustive swimming combined with diethylnitrosamine induction. UHPLC-Q-Orbitrap-MS was employed to analysis the components of PG both in vitro and in vivo using the QDLC rat model. Multi-omics analysis combining network pharmacology, metabolomics, and transcriptomics was used to identify potential pharmacodynamic components and investigate potential mechanism of action. The results were further validated using transmission electron microscopy, immunofluorescence, and Western blotting. Molecular docking was performed to explore interactions between major PG constituents and core pathway proteins. A total of 52 and 14 PG components were identified in vitro and from the livers of QDLC rat models, respectively. Integrated multi-omics and in vivo validation results indicate that PG alleviates QDLC by regulating the HIF-1α/PPARα-mediated fatty acid oxidation (FAO) signaling axis and mitochondrial dysfunction in the liver, with Rk3 playing a critical role in this process. The alleviating effect of PG on QDLC may be attributed to the activation of the HIF-1α/PPARα-mediated FAO signaling axis, which improves mitochondrial dysfunction in the liver. • An integrative approach combining network pharmacology, metabolomics, and transcriptomics was applied to investigate the mechanisms of Panax ginseng extract in alleviating Qi deficiency liver cancer. • The HIF-1α/PPARα-mediated fatty acid oxidation (FAO) signaling axis and mitochondrial dysfunction in the liver have been confirmed to be key regulatory axes in the PG-mediated alleviation of QDLC. • Ginsenoside Rk3 exhibits significant efficacy in alleviating QDLC.