O-GlcNAcylation of YBX1 drives a glycolysis-histone lactylation feedback loop in hepatocellular carcinoma

Metabolic reprogramming is a hallmark of tumorigenesis and progression, with alterations in glucose metabolism, often referred to as the Warburg effect, playing a central role. This shift allows tumor cells to rapidly acquire energy and generate essential metabolic intermediates, thereby supporting enhanced growth. Despite its significance, the mechanisms by which tumor cells upregulate glycolysis remain inadequately understood. In this study, we report that YBX1 is highly expressed in hepatocellular carcinoma (HCC) and is closely associated with glycolysis. We show that YBX1 is modified by O-linked N-acetylglucosamine (O-GlcNAc) at threonine 57 (T57), which stabilizes the protein and increases its expression. This modification also promotes the phosphorylation of YBX1 at serine 102, facilitating its nuclear translocation. Consequently, this process enhances the transcription of glycolysis-related genes and stimulates lactate production. Moreover, YBX1 activates the transcription of P300, which in turn drives the lactylation of histones, particularly H3K18la. Cleavage Under Targets and Tagmentation (CUT&Tag) analysis reveals that H3K18 lactylation positively regulates YBX1 gene transcription. Our findings establish a positive feedback loop involving YBX1, glycolysis, and H3K18 lactylation that accelerates HCC progression. Disrupting this feedback loop may provide a novel therapeutic strategy for HCC.