PGM3-Driven Hexosamine Biosynthesis Facilitates Hepatocellular Carcinoma Progression through YBX1 O-GlcNAcylation (Untargeted metabolomics)

ABSTRACT: Phosphoglucomutase 3 (PGM3) is one of the rate-limiting enzymes in the hexosamine biosynthesis pathway (HBP) and a key regulator of HBP metabolic flux. Despite the functional role of PGM3 has been validated in various tumors, its function and molecular mechanism in hepatocellular carcinoma (HCC) remain to be elucidated. This study found that PGM3 expression is upregulated in HCC tissues, and high PGM3 expression is closely associated with poor prognosis in HCC patients. In vitro and in vivo results demonstrated that PGM3 enhances UDP-GlcNAc synthesis and protein O-GlcNAcylation, thereby promoting HCC proliferation, migration, and invasion. Further O-GlcNAcylomic sequencing of HCC cells identified Y-box binding protein 1 (YBX1) as a key substrate for PGM3-mediated O-GlcNAcylation. Notably, O-GlcNAcylation of YBX1 at a specific serine residue (Ser165) enhances its nuclear translocation. Additionally, we validated that FR054, a novel reported PGM3 inhibitor, retards HCC progression by diminishing PGM3-mediated O-GlcNAcylation. These interventions effectively inhibit HCC malignant progression. Collectively, our findings reveal the potential therapeutic value of targeting the PGM3-HBP-YBX1 signaling axis in HCC treatment.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS15545 | MetaboLights | 2026-09-03

REPOSITORIES: MetaboLights