Unraveling Riboflavin-Mediated Mitochondrial Modulation as a Therapeutic Pathway in Neurological Disorders: An Integrative Systematic Review

Mitochondrial dysfunction is recognized as a key pathophysiological mechanism in neurodegenerative diseases. Alterations in mitochondrial dynamics-including imbalances in fission and fusion, impaired biogenesis, and disrupted mitophagy-contribute to the onset and progression of neurological disorders. In this context, mitochondrial modulation has emerged as a promising therapeutic strategy. This systematic review examined the role of riboflavin, a water-soluble vitamin and essential mitochondrial cofactor, in neurological interventions through mitochondrial modulation, with emphasis on elucidating the underlying molecular mechanisms. A search of the PubMed, Embase, Scopus, and Web of Science databases identified 23 eligible studies, comprising 6 in vitro experiments, 10 rodent models, and 7 clinical trials. These studies evaluated the effects of riboflavin in monogenic, neurodegenerative, and demyelinating mitochondrial diseases, cerebrovascular/hypoxic injury, and pain/migraine. Clinical evidence indicated that riboflavin may regulate oxidative stress in stroke and perinatal asphyxia, with associated functional improvements. Preclinical findings revealed mechanisms of action involving energy homeostasis, cell cycle regulation, and mitochondrial dynamics across monogenic mitochondrial disorders, neurodegenerative diseases, hypoxic injury, and models of pain and migraine. Possibly through mitochondrial modulation, riboflavin appeared to reduce α-synuclein aggregation in Parkinson's disease, increase the number of tyrosine-hydroxylase-positive neurons in Alzheimer's disease models, enhance neuronal survival in Brown-Vialetto-Van Laere and Huntington's disease models, and normalize neuronal excitability in ataxia and migraine. In contrast, no therapeutic effects were observed in demyelinating diseases. Overall, the findings suggest that riboflavin may promote neuroprotection through redox modulation and gene regulation, stabilization of membrane potential, and enhanced mitochondrial complex activity via flavin cofactors, ultimately supporting neuronal metabolism and functional outcomes. Despite advances in mechanistic understanding, clinical applications in humans remain insufficiently defined for most conditions, with clearer dosage regimens currently established only for stroke and migraine.