Hyaluronic acid promotes hepatocellular carcinoma proliferation by upregulating CD44 expression and enhancing glucose metabolism flux

Hepatocellular carcinoma (HCC), known for its high malignancy, exhibits a critical feature in its progression through the alteration of metabolic pathways. Our study initially observed an increase in hyaluronic acid (HA) secretion by HCC cells through ELISA analysis. Further protein–protein interaction (PPI) network analysis highlighted CD44 and HAS2 as critical nodes, suggesting their pivotal roles in HA metabolism. Silencing of HAS2 markedly reduced HA production and suppressed cell proliferation, whereas overexpression of HAS2 enhanced HA synthesis and promoted cellular growth. Moreover, we found that HA, through binding to CD44, activates the downstream PI3K/AKT/MYC signaling pathway. This activation not only upregulates MYC expression but also leads to an increase in GLUT1 expression level. As a transcription factor for GLUT1, MYC directly facilitates its expression, thereby enhancing glucose uptake and glycolytic activity. Additionally, CD44 can directly interact with GLUT1, further promoting glucose flux. These mechanisms collectively boost anaerobic glycolysis and the hexosamine biosynthetic pathway (HBP), providing essential energy and metabolites for rapid liver cell proliferation. Our findings not only elucidate the central role of HA in regulating cellular metabolism but also lay a solid theoretical foundation for developing therapeutic strategies targeting HA-related metabolic pathways.