Bcl-2 as a Double-edged Sword for the Treatment of Multiple Sclerosis: A Systematic Review

Introduction: Multiple sclerosis (MS) is a chronic immune-mediated neurodegenerative disease that involves inflammation, demyelination, and neuronal loss. The B-cell lymphoma 2 (Bcl-2) protein family regulates intrinsic apoptotic pathways and may impact disease progression via effects on immune cell survival and neuroprotection. Methods: To review current evidence on the role of Bcl-2 and its modulators in MS. Englishlanguage, clinical and preclinical studies (1998–October 2025) were retrieved from PubMed, Google Scholar, and other databases. Results: Clinical studies show that peripheral B lymphocytes and autoreactive T cells in relapsingremitting MS often exhibit increased Bcl-2 expression, leading to enhanced resistance to apoptosis and persistence of inflammatory immune responses. Factors such as leptin can further increase Bcl-2 levels in autoreactive T cells. In experimental studies, several interventions, including interferon-β1a, solanesol, green tea and pumpkin oils, β-hydroxybutyrate, cannabidiol, galantamine, melatonin, rifampicin, and rapamycin, were shown to modulate apoptotic pathways by increasing Bcl-2 expression or reducing the Bax/Bcl-2 ratio and caspase-3 activation in neurons. These changes were often accompanied by reduced inflammatory cytokines, decreased oxidative stress, improved neuronal survival, and attenuation of demyelination in MS models. Discussion: Overall, the collected evidence suggests that modulation of the Bcl-2 balance represents an important mechanism underlying both immune regulation and neuroprotection in MS. Conclusion: While modulating Bcl-2 pathways can be effective in MS, future research should aim to provide greater clarification and to design precision-based drugs capable of neuroprotective effects.