Positive feedback loop via HIF-1α lactylation driven by kynurenine promotes glycolysis.

Tryptophan metabolism undergoes marked alterations in OSCC, leading to an abnormal accumulation of the metabolite kynurenine. Nonetheless, how kynurenine, a key intermediate of tryptophan metabolism, contributes to tumor metabolic reprogramming is still not well clarified. Here, we identify Kyn as a metabolic signal that drives glycolytic reprogramming and promotes tumor progression. Mechanistically, Kyn functionally associates with AKT and enhances AKT-dependent mTOR phosphorylation, leading to subsequent activation of the mTOR which facilitates the dissociation of eIF4EBP1 from eIF4E, thereby enhancing cap-dependent translation of HIF-1α. Elevated HIF-1α upregulates glycolytic enzymes, accelerating glycolytic flux and increasing lactate production. The accumulated lactate in turn stabilizes HIF-1α through lysine lactylation, thereby establishing a reinforcing feedback cycle that enhances glycolytic activity and supports continuous tumor expansion. Collectively, our results uncover an unappreciated metabolic regulatory loop in which kynurenine promotes glycolysis via AKT/mTOR-mediated translational activation and HIF-1α lactylation, highlighting a mechanistic link between tryptophan metabolism and glucose metabolism. These insights provide a rationale for combined therapeutic strategies targeting the kynurenine pathway and glycolysis in OSCC.