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

Authors

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

Published in

Oncogene. Jul 23, 2026. Epub Jul 23, 2026.

Abstract

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.

PMID:
42493543
Bibliographic data and abstract were imported from PubMed on 24 Jul 2026.

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