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 inhibits HCC cell proliferation and migration in a dose-dependent manner 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 adenosine triphosphate (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, with the combined GlcN and lenvatinib treatment showing markedly enhanced HCC suppression than monotherapies. 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.