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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年7月23日

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  • Shuoqi Lin,
  • Yuxiang Yan,
  • Junlin Zhou,
  • Genggeng Zheng,
  • Tesen Liao,
  • Youguang Lu,
  • Bohua Su,
  • Dali Zheng

摘要

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.