METTL15-mediated m4C modification regulates glucose metabolic reprogramming via c-Myc-dependent mechanisms and promotes hepatocellular carcinoma progression.

Although aerobic glycolysis is a hallmark of hepatocellular carcinoma (HCC) progression, the underlying epitranscriptomic mechanisms remain poorly understood. Here, we identify METTL15, an N4-methylcytidine (m4C) RNA methyltransferase, as a novel oncogenic driver of this metabolic reprogramming. METTL15 is significantly upregulated in HCC tissues and cell lines, with high expression predicting poor clinical outcomes. Functional assays demonstrate that METTL15 promotes HCC cell proliferation and metastasis both in vitro and in vivo. Mechanistically, METTL15 interacts with c-Myc mRNA and modulates its expression through a mechanism potentially involving m4C-dependent translational regulation, thereby accelerating glycolytic flux. Together, our findings establish METTL15 as a critical epitranscriptomic regulator of tumor aerobic glycolysis and highlight its promise as a therapeutic target for HCC.