Redox Imbalance in Multiple Sclerosis: From Oxidative Injury to Biomarkers and Therapeutic Targets—A Systematic Review

Oxidative stress connects the inflammatory and the neurodegenerative components of multiple sclerosis, and redox markers have been proposed both for monitoring the disease and as targets for treatment. Individual studies, however, have reached divergent conclusions. In this systematic review, we searched PubMed, Scopus and Web of Science Core Collection for human studies published between 1 January 2019 and 11 April 2026 (PROSPERO CRD420261440796, registered retrospectively) and included 73 studies, 71 from the 23,027 database records and two from our earlier systematic review of fluid biomarkers in MS: forty-one case–control studies, six analytical cross-sectional studies, one prospective cohort, sixteen randomized trials and nine non-randomized or single-arm interventional studies. Circulating nitric oxide metabolites were the most consistent abnormality, higher in patients than in controls in all eight studies that measured them in blood, whether or not patients were receiving treatment, but not in cerebrospinal fluid. Antioxidant reserve was commonly reduced: total antioxidant capacity was lower in 13 of 20 studies, and thiols and glutathione peroxidase were lower in every study that measured them, whereas the antioxidant enzymes proved dysregulated rather than depleted, with superoxide dismutase tending to rise. Protein oxidation was raised in most cohorts, but advanced oxidation protein products, which discriminated patients from controls with an area under the curve of 0.948 in one cohort, were unchanged or lower in two others. Direction of change depended strongly on the compartment sampled and the assay used. 8-Hydroxy-2′-deoxyguanosine was higher in cerebrospinal fluid and urine but lower in serum. In two cohorts, antioxidant capacity measured with the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical-scavenging assay (ABTS) and with the ferric reducing ability of plasma assay (FRAP) diverged in the same samples, in opposite directions. Antioxidant supplements and disease-modifying therapies altered redox status in most interventional studies, whereas the two exercise trials disagreed, and the changes were frequently transient and did not always accompany clinical improvement. Rated using a GRADE-informed approach adapted for this type of synthesis, the certainty of the evidence is very low for every marker assessed; nitric oxide metabolites, cerebrospinal fluid antioxidative capacity and total antioxidant capacity, measured by a specified assay, are the most reasonable candidates for prospective validation, and none is ready for clinical practice.