Lysine lactylation in glioma: from metabolic stress to epigenetic remodeling and therapeutic resistance.

Authors

Xiaosong Hu, Li Yang, Yanghao Hu, Hongjuan Cui

Published in

Frontiers in cell and developmental biology. Volume 14. Pages 1821274. Epub Oct 12, 2026.

Abstract

Glioma is characterized by profound metabolic reprogramming and sustained lactate accumulation; however, the mechanisms by which lactate-rich metabolic stress is translated into stable malignant phenotypes remain incompletely understood. Lysine lactylation (Kla), a recently identified post-translational modification, has emerged as a critical nexus linking lactate metabolism to durable epigenetic and protein-state adaptations. In glioma, accumulating evidence indicates that Kla contributes to multiple dimensions of tumor biology, including oncogenic transcriptional activation, glioma stem-like cell (GSC) maintenance, immunosuppressive remodeling, and therapeutic resistance. Mechanistically, histone Kla rewires metabolic stress-responsive transcriptional programs, whereas non-histone Kla executes rapid, transcription-independent responses by directly modifying key regulatory proteins involved in DNA repair, signal transduction, and metabolic adaptation. This review systematically summarizes current progress on the lactate-Kla axis in glioma, encompassing the basis of lactate metabolism, the molecular regulatory network of Kla, and the distinct yet coordinated functions of histone and non-histone lactylation. We further discuss how Kla contributes to temozolomide (TMZ) resistance, radioresistance, and chemoradiotherapy adaptation, and outline a hierarchical therapeutic framework targeting this pathway. Despite rapid advances, important areas requiring further investigation include subtype-specific variation in lactate-Kla biology and the potential crosstalk between Kla and other post-translational modifications. A better understanding of these issues will help define the biological significance of the lactate-Kla axis and guide the future development of lactylation-based therapeutic strategies in glioma.

PMID:
42928918
Bibliographic data and abstract were imported from PubMed on 26 Oct 2026.

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