Targeting post-translational modifications to overcome glioblastoma therapy resistance: emerging strategies and natural compounds

Post-translational modifications (PTMs) regulate multiple mechanisms associated with glioblastoma (GBM) therapy resistance, which remains a major challenge in GBM treatment. Some resistance mechanisms involve genetic heterogeneity, glioblastoma stem cells, the tumor microenvironment, autophagy, metabolic reprogramming, vascular adaptation, and altered transcriptional regulation. By regulating protein activity, stability, localization, interactions, and signaling, PTMs can influence several of these processes and affect treatment response. This review examines the roles of phosphorylation, ubiquitination and ubiquitin-like modifications, acetylation, methylation, and glycosylation in resistance to temozolomide, radiotherapy, and targeted therapies. We further discuss emerging PTMs, including lactylation, succinylation, and UFMylation, for which evidence linking individual modifications to therapeutic resistance ranges from direct resistance mechanisms to effects primarily associated with GBM biology. PTM crosstalk is also discussed in the context of DNA repair, redox homeostasis, metabolism, glioblastoma stem cell maintenance, and therapy response. Finally, we examine pharmacological targeting of PTM-regulating enzymes and pathways and the effects of natural bioactive compounds on PTM-dependent mechanisms.