Molecular Mechanisms of Cell Death in Multiple Sclerosis: Emerging Targets for Therapeutic Intervention

Multiple sclerosis (MS) is an autoimmune disease that impacts the brain and spinal cord, which constitute the Central Nervous System (CNS), causing demyelination, inflammation, and neurodegeneration. It is a prevalent disease with limited biomarkers and treatment options. Emerging evidence, primarily from preclinical models like experimental autoimmune encephalomyelitis (EAE) and supported by human tissue studies, has explored the link between MS and various cell death pathways, including apoptosis, autophagy, necroptosis, ferroptosis, and pyroptosis. The involvement of these pathways in MS suggests the potential use of their associated molecules as biomarkers and the intervention in these pathways as therapeutic strategies. This review highlights the double-edged nature of apoptosis and autophagy: their inhibition or stimulation can either reduce or exacerbate MS progression. On the other hand, inhibiting necroptosis, ferroptosis, and pyroptosis may consistently reduce MS progression. More rigorous studies are needed to elucidate the complex relationship among MS, apoptosis, and autophagy. Molecules involved in necroptosis (such as RIPK1, RIPK3, and MLKL), ferroptosis (such as GPX4 and lipid peroxides), and pyroptosis (such as NLRP3, caspase-1, and gasdermin D) show promise as potential biomarkers for MS. Inhibitors targeting these pathways, including necrostatins (for necroptosis), ferrostatins and liproxstatins (for ferroptosis), and NLRP3 inhibitors (for pyroptosis), may offer new approaches for reducing disease progression. A comprehensive strategy that incorporates both reliable biomarkers and targeted treatments would significantly improve MS management in terms of diagnosis, monitoring, and treatment.