From Demyelination to Intervention: Natural Compounds as Emerging Therapeutic Targets in Multiple Sclerosis Neuroinflammation.

Multiple sclerosis (MS) is a chronic immune-mediated inflammatory demyelinating disease of the central nervous system (CNS), characterized by multifocal lesions, axonal damage, and progressive neurological dysfunction, imposing a heavy burden on patients and healthcare systems. While T lymphocytes have long been regarded as central to MS pathogenesis, accumulating evidence underscores the pivotal role of B lymphocytes and dysregulated cytokine networks (e.g., Th17/IL-17 and NF-κB pathways) in driving disease initiation and progression. Despite advances in symptomatic management and disease-modifying therapies (DMTs), clinical interventions for MS remain constrained by severe side effects, drug dependency, and suboptimal long-term efficacy, highlighting an urgent unmet need for novel therapeutic strategies. Natural compounds (e.g., alkaloids, flavonoids, terpenoids, and polyphenols) have emerged as promising candidates owing to their inherent biocompatibility, favorable safety profiles, and multi-targeted regulatory effects on neuroinflammation. This review critically synthesizes and evaluates current evidence on the therapeutic potential of natural compounds in MS, with a focus on cross-compound class integration of core common pathways (e.g., NF-κB inhibition and Th17/Treg balance modulation) rather than isolated mechanism descriptions. We explicitly compare the strength of evidence across different natural compounds, clarifying which findings are well-substantiated versus preliminary. Notably, we emphasize the inherent limitations of experimental autoimmune encephalomyelitis (EAE) models in recapitulating human MS pathophysiology (e.g., interspecies immune divergence and disease heterogeneity) and integrate or at least reference relevant clinical/epidemiological evidence to enhance translational relevance. Finally, we outline key future perspectives, including the integration of natural products with existing DMTs, challenges in clinical trial design, and prospects of combination therapies, aiming to provide a directional framework for advancing natural compounds from preclinical exploration to actionable clinical therapeutic targets in MS and enhancing the translational impact of this field.