Ononin suppresses proliferation and glycolysis in hepatocellular carcinoma via the EGFR/PI3K/AKT signaling pathway

Abstract This study investigated the inhibitory effect of Ononin on hepatocellular carcinoma (HCC) and to elucidate its molecular mechanisms. CCK-8, EdU, colony formation, and Transwell assays were used to assess HCC cell proliferation, migration, and invasion. Western blotting and RT-qPCR analyzed protein and gene expression. Rescue experiments were conducted using EGFR knockdown, overexpression, and IGF-1. A xenograft mouse model evaluated the in vivo efficacy. Ononin dose-dependently suppressed the proliferation, colony formation, migration, and invasion of HCC cells. Mechanistically, Ononin treatment reduced the phosphorylation levels of EGFR, PI3K, and AKT, downregulated the expression of several key glycolytic enzymes including HK2 and PKM2, and concurrently decreased cellular glucose consumption, lactate production, and ATP generation. EGFR knockdown enhanced these inhibitory effects of Ononin, whereas EGFR overexpression or IGF-1-mediated pathway activation partially reversed them. In vivo experiments confirmed that Ononin significantly inhibited xenograft tumor growth and reduced the levels of p-EGFR, p-PI3K, p-AKT and glycolytic enzymes within the tumor tissues. Ononin may exert anti-HCC effects by inhibiting the EGFR/PI3K/AKT signaling pathway and subsequently interfering with downstream glycolytic metabolism. This study provides experimental evidence supporting Ononin as a potential candidate compound for HCC therapy.