The dual role of mTOR in multiple sclerosis pathophysiology: a systematic review

Clinical Snapshot

Key Findings

• P Value: Not reported at the review level

• Effect Size: Not quantified; qualitative synthesis only. No pooled effect sizes reported across the 90 included studies

• Primary Outcome: mTOR plays a dual, context-dependent role in MS pathophysiology: inhibition of mTOR reduces pro-inflammatory signalling and may enhance autophagy (neuroprotective), while activation of mTOR promotes oligodendrocyte differentiation, maturation, and remyelination

• Nnt Or Sensitivity: Not calculable from this qualitative systematic review. No NNT, sensitivity, specificity, or hazard ratio data are synthesised at the review level

• Confidence Interval: Not applicable; no meta-analysis performed

Clinical Application

Direct clinical application is not currently feasible. The dual role of mTOR — where inhibition suppresses inflammation but impairs remyelination, and activation promotes remyelination but exacerbates inflammation — creates a therapeutic paradox that cannot be resolved without disease-stage-specific, temporally controlled intervention strategies. No approved mTOR-targeted therapy exists specifically for MS. Existing mTOR inhibitors (rapamycin, everolimus) carry significant immunosuppressive and metabolic side-effect profiles that complicate use in MS. In Australia, no mTOR inhibitor is currently PBS-listed or TGA-approved for the treatment of MS. Existing disease-modifying therapies (DMTs) for MS on the PBS include interferons, glatiramer acetate, natalizumab, fingolimod, ocrelizumab, and cladribine, among others. RACGP and MS Australia guidelines do not currently recommend mTOR-targeted therapy. This review provides mechanistic rationale for future clinical trial design but does not support changes to current Australian prescribing practice. Australian neurologists and MS specialists should be aware of the dual-role concept when interpreting emerging trial data on mTOR modulators in neuroinflammatory disease. Adults with relapsing-remitting or progressive multiple sclerosis where mTOR-targeted therapies (e.g., rapamycin/sirolimus analogues) might be considered as adjunctive neuroprotective or remyelinating agents. Findings are most directly applicable to research contexts rather than current clinical practice.

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by demyelination, neuroinflammation, and progressive neurodegeneration. The mechanistic target of rapamycin (mTOR) pathway plays a key role in regulating immune responses, cell metabolism, autophagy, and repair processes. Although the role of mTOR in neurodegeneration has been explored in previous reviews, a systematic assessment of its function in MS across different models is still lacking. This systematic review aimed to examine the role of mTOR signaling in the pathophysiology of MS. Following Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, we screened preclinical and clinical studies using two databases and assessed the risk of bias specific to the study types. A total of 189 records were identified, of which 90 met the inclusion criteria for qualitative analysis. Studies using in vitro and in vivo (mainly rodent models, both sexes) models of MS, as well as MS patient tissue or data, consistently demonstrated that mTOR is involved in the MS-related processes neuroinflammation, myelination, autophagy, gliosis, mitochondrial dysfunction, and oxidative stress. mTOR inhibition reduces pro-inflammatory signaling and may enhance autophagy, offering neuroprotection. In contrast, activation of mTOR promotes remyelination by enhancing oligodendrocyte differentiation and maturation. These remyelinating effects may be masked in inflammatory environments, because activation of mTOR supports immune cell expansion and glial reactivity, inducing inflammation and oxidative stress. Overall, our findings underscore a dual role of mTOR in MS pathology, with important implications for disease stage and timing of intervention. Although mTOR is mechanistically important in MS, its therapeutic modulation is unlikely to be readily clinically translatable without a substantial risk of unintended and context-dependent effects.

References

1. 1.Koks, F., Reubens, F., van der Zee, H., & Briedé, J. J. (2025). The dual role of mTOR in multiple sclerosis pathophysiology: a systematic review. Molecular Therapy: Methods & Clinical Development [listed as Journal of Neurology; bibliographic discrepancy noted]. https://doi.org/10.1016/j.omtm.2025.101504