Lysine lactylation in glioma: from metabolic stress to epigenetic remodeling and therapeutic resistance.
- 1State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing, China.
- 2Jinfeng Laboratory, Chongqing, China.
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.
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BibTeX
@article{hu2026lysine,
title = {{Lysine lactylation in glioma: from metabolic stress to epigenetic remodeling and therapeutic resistance.}},
author = {Xiaosong Hu and Li Yang and Yanghao Hu and Hongjuan Cui},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1821274},
url = {https://europepmc.org/article/MED/42928918},
note = {CC BY},
}
RIS
TY - JOUR
TI - Lysine lactylation in glioma: from metabolic stress to epigenetic remodeling and therapeutic resistance.
AU - Xiaosong Hu
AU - Li Yang
AU - Yanghao Hu
AU - Hongjuan Cui
PY - 2026
DA - 2026/10/12
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1821274
UR - https://europepmc.org/article/MED/42928918
AB - 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.
SN - 2296-634X
ER -