Glucosamine suppresses hepatocellular carcinoma progression through dual inhibition of cell cycle progression and nucleotide metabolism

Hepatocellular carcinoma (HCC) is a prevalent and aggressive liver cancer with limited treatment options and poor prognosis. Glucosamine (GlcN), a widely used dietary supplement, demonstrates anti-inflammatory properties but its antitumor potential in HCC remains unknown. Here, we report that GlcN concentration-dependently inhibits HCC cell proliferation and migration in vitro and suppresses orthotopic tumor growth in vivo. Mechanistically, integrated transcriptomics and functional validation revealed that GlcN induces cell cycle arrest in G0/G1 phase by inhibition of E2F1 transcriptional activity. Untargeted metabolomics identified profound nucleotide metabolism disruption, characterized by ATP depletion, and partial reversal via nucleoside rescue. Notably, GlcN potentiates the inhibitory efficacy of lenvatinib both in vitro and in vivo. This synergistic effect was further validated in murine models, where combined GlcN and lenvatinib treatment markedly enhanced HCC suppression compared to monotherapy. Collectively, our findings suggest GlcN as a potential therapeutic agent for HCC and underscore its chemosensitizing potential when combined with lenvatinib. Given GlcN's established clinical safety, this combination offers a translatable strategy for HCC therapy.