The dual role of the PI3K/AKT/mTOR axis in glial cell survival and neuroinflammation.

Multiple sclerosis is characterized by a triad of inflammation, demyelination, and neurodegeneration, yet current disease-modifying therapies are limited in their ability to halt progressive neurodegeneration or promote remyelination. The PI3K/AKT/mTOR signaling pathway is a master regulator of these divergent cellular processes and therefore represents a biological paradox in multiple sclerosis. In the pathogenic facet of the disease, activation of this axis supports the differentiation and effector functions of pro-inflammatory T- and B-cells and contributes to inflammatory programs in microglia and macrophages. In the regenerative facet, physiological PI3K/AKT/mTOR activity is required for oligodendrocyte precursor-cell survival, differentiation, myelin synthesis, and maintenance of myelin integrity. Astrocytic signaling adds another layer of context-dependence, with pathway activity influencing reactive gliosis and the inflammatory or reparative properties of the lesion environment. Consequently, systemic inhibition of the pathway may suppress neuroinflammation while simultaneously interfering with endogenous repair. This review therefore considers PI3K/AKT/mTOR axis according to these opposing pathogenic and protective functions, highlighting the importance of cell type, disease stage, and treatment timing. Precision strategies capable of selectively suppressing inflammatory signaling while preserving or restoring pro-regenerative activity, potentially through cell-specific molecular targets, may provide a more rational therapeutic approach than generalized pathway inhibition.