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

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.