Complement dysregulation in multiple sclerosis: emerging mechanisms and translational therapeutic opportunities

The complement system is a conserved network of plasma and membrane-associated proteins that supports immune defense and tissue homeostasis. In multiple sclerosis (MS), persistent complement activation contributes to neuroinflammation, demyelination, and axonal injury. However, the translation of complement-targeted therapies for MS treatment has been limited, largely due to uncertainty surrounding the complex and context-dependent roles of complement pathways within the central nervous system. This review integrates the latest preclinical and clinical insights to delineate pathogenic and reparative complement pathways and to support the stratification of MS phenotypes using complement biomarkers and signatures. We further review approved and emerging complement inhibitors with neurological relevance, focusing on their translational implications for MS. Together, this integrated framework may guide the rational design of future complement-targeted MS trials.