SIRT1-mediated NSUN2 delactylation restricts hypopharyngeal squamous cell carcinoma progression by suppressing m5C-dependent asparagine biosynthesis

The mechanisms by which the glycolytic microenvironment orchestrates amino acid metabolic reprogramming via protein lactylation remain a fundamental yet unresolved question in cancer biology. Here, we identify SIRT1 as a pivotal tumor suppressor in hypopharyngeal squamous cell carcinoma (HSCC) that is frequently downregulated to facilitate malignant progression. Mechanistically, SIRT1 functions as a direct delactylase of the RNA methyltransferase NSUN2, specifically targeting the K470 residue. We demonstrate that SIRT1 deficiency leads to NSUN2 hyperlactylation, which uniquely enhances its catalytic activity toward the m 5 C methylation of ASNS mRNA, thereby driving de novo asparagine biosynthesis to fuel HSCC proliferation. This SIRT1/NSUN2/ASNS axis establishes a previously uncharacterized molecular bridge linking lactate-driven post-translational modifications to RNA epigenetics and amino acid remodeling. Furthermore, pharmacological activation of SIRT1 exhibits potent synergistic anticancer effects when combined with L-asparaginase (ASNase), offering a sophisticated therapeutic strategy to overcome metabolic adaptation in HSCC.