Dysregulation of post-translational modifications in glioma: advances in pathological mechanisms and clinical targeting strategies

Post-translational modifications (PTMs) are key epigenetic regulators modulating glioma initiation, progression, and therapeutic response by regulating target proteins’ properties. Major PTM subtypes (phosphorylation, ubiquitination, SUMOylation, acetylation, succinylation, lactylation, glycosylation, and methylation) have context-dependent roles; their dysregulation disrupts homeostasis, promoting oncogene activation, stemness, and TMZ resistance. However, PTM cross-regulation, redundancy, and clinical translation remain unclear. This review adopts a comprehensive perspective to summarize advances on PTM dysregulations in gliomas. It synthesizes findings on the regulatory roles of each major PTM subtype in glioma pathophysiology, their functional impacts on glioma biological processes, and the implications of PTM dysregulation in therapeutic resistance. Phosphorylation drives critical cell signaling transduction, like mTOR and EGFR signaling cascades. Ubiquitination regulates the stability of key oncoproteins, and SUMOylation regulates nuclear processes and protein localization. Acetylation, succinylation, and lactylation are metabolite-dependent PTMs, which are closely coupled to glioma metabolic reprogramming. Histone methylation dynamically remodels chromatin accessibility to regulate gene transcription, while non-histone methylation bridges cellular signaling with epigenetic regulation. Glycosylation enhances tumor cell adhesion and invasiveness. Notably, dysregulation of these PTMs is consistently associated with glioma progression and TMZ resistance, yet the cross-regulatory networks and functional redundancy among these PTMs remain understudied. This review systematically integrates current understanding of PTM dysregulation in gliomas and highlights their coordinated regulatory roles. Also, we identify unresolved gaps in PTM crosstalk and clinical translation and provide a foundation for developing PTM-targeted precision therapies. Not applicable.