Specnuezhenide from Ligustrum sinense Lour. inhibits liver cancer by suppressing glycolysis: a multi-omics study

This study investigates the anti-liver cancer mechanism of Ligustrum sinense Lour. (XDQ), a Tujia ethnomedicine, using a multi-omics approach. In H22 tumor-bearing mice, XDQ significantly inhibited tumor growth by up to 79.64% without observable toxicity. UPLC-Q/TOF-MS analysis identified 66 compounds in XDQ, with five—specnuezhenide, prosapogenin A, oleuropein, oxyberberine, and pseudoanisatin—detected in both serum and tumor tissues, indicating good bioavailability. Integrated network pharmacology, transcriptomics, and proteomics analyses consistently revealed that XDQ's anti-tumor effect is mediated through the suppression of glycolysis. This was evidenced by the downregulation of key glycolytic enzymes, including GPI, PGAM1, PGK1, and PKM2, and a subsequent decrease in glucose consumption and lactate production. Molecular docking identified specnuezhenide as the component with the strongest binding affinity to the rate-limiting enzyme GPI. In vitro validation confirmed that specnuezhenide inhibits glycolysis and suppresses the expression of glycolysis enzymes in liver cancer cells. Our findings demonstrate that XDQ exerts its anti-liver cancer effects primarily by inhibiting tumor glycolysis, with specnuezhenide being a key active constituent, providing a scientific basis for developing XDQ as a potential therapeutic agent.