O-GlcNAc cycling in neuroinflammation: From molecular mechanisms and therapeutic perspectives

O-GlcNAcylation is a dynamic post-translational modification that regulates diverse cellular processes by modifying nuclear and cytoplasmic proteins in response to metabolic cues. This modification is controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which together maintain O-GlcNAc cycling. Emerging evidence indicates that O-GlcNAcylation plays a critical role in modulating neuroinflammation, a key pathological feature of many neurological disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. O-GlcNAcylation modulates several components of the neuroinflammatory cascade, including glial activation, cytokine production, oxidative stress, and inflammasome assembly, primarily through its influence on transcription factors such as NF-κB and STATs, as well as key signaling pathways like MAPK. In this review, we critically evaluate current insights into the mechanisms by which O-GlcNAc cycling regulates neuroinflammatory processes and discuss recent advances in therapeutic strategies targeting O-GlcNAc metabolism. These insights underscore the potential of modulating O-GlcNAcylation as a novel strategy for controlling neuroinflammation across a range of disease contexts.