Differential microRNA Expression Reveals Sex-Specific Neuroinflammatory and Neurodegenerative Pathways in MS

Relapsing-remitting multiple sclerosis (RRMS) exhibits clear sex-based disparities: females have higher incidence and inflammatory activity, whereas males have lower incidence, yet experience an accelerated disease course of neurodegeneration and disability accumulation. MicroRNAs (miRNAs). Key epigenetic regulators of immune and neuronal pathways may contribute to these differences, but sex is rarely examined as a primary biological variable in MS miRNA research. This exploratory pilot study characterized sex-specific miRNA expression in treatment-naïve individuals with RRMS using samples from 46 participants (17 males and 17 females with RRMS; 6 male and 6 female healthy controls) obtained from the Accelerated Cure Project biorepository. miRNA expression was quantified using the NanoString nCounter Human v3 panel, and differential expression (p < 0.05, fold-change ≥1.3) was evaluated across four comparisons: Multiple sclerosis (MS) females vs. MS males; sex-matched MS vs. control groups; and female vs. male healthy controls. Distinct sex-biased miRNA signatures emerged. Males with RRMS demonstrated dysregulation of immune-associated miRNAs, including coordinated changes in the miR-29, miR-30, and miR-199 families. Females with RRMS exhibited consistent downregulation of miR-941 and differential expression of immune-associated miRNAs including miR-223-3p, miR-485-3p, and miR-199a-5p. Several immune-regulatory miRNAs, including miR-223-3p, miR-146a-5p, miR-196b-5p, and miR-183-5p, were differentially expressed in both healthy controls and disease-related comparisons, suggesting that sexually dimorphic immune regulatory programs may precede disease onset. These findings indicate that disease-associated miRNA alterations are superimposed on pre-existing sex-specific immune networks and underscore the importance of incorporating sex as a biological variable in biomarker discovery and precision medicine for MS.