Natural flavonoids in multiple sclerosis: molecular insights and emerging therapeutic strategies.

Multiple sclerosis is a chronic immune mediated disease in which current disease modifying therapies reduce inflammatory relapses but incompletely address neurodegeneration and remyelination. Natural flavonoids are pleiotropic polyphenols that can modulate immune and glial signaling, oxidative stress, and mitochondrial function. This review synthesizes evidence from experimental models and human studies on flavonoids relevant to multiple sclerosis, emphasizing mechanisms involving NF-κB, Nrf2, inflammasome signaling, and microglia and macrophage polarization that shape oligodendrocyte precursor cell differentiation and remyelination permissiveness. We highlight structure activity features, metabolism and glycosylation that govern exposure, and discuss translational barriers including low and variable bioavailability, limited blood brain barrier penetration, standardization, and potential interactions with approved therapies. Emerging enabling strategies are reviewed, including lipid and polymeric nanocarriers, stimuli responsive delivery, systems biology and multi omics target discovery, network pharmacology for multi target prioritization, microbiome informed approaches, and synthetic biology for scalable production and derivative optimization. Overall, preclinical studies consistently support anti-inflammatory and neuroprotective effects, while clinical evidence remains early and mixed, underscoring the need for well powered trials with pharmacokinetic and pharmacodynamic endpoints.