MicroRNA biomarkers for JC virus reactivation and progressive multifocal leukoencephalopathy in natalizumab-treated multiple sclerosis patients: a systematic review.

Background PML from JC polyomavirus (JCV) reactivation is a major safety threat in multiple sclerosis, especially with natalizumab. However, it remains unknown which microRNA (miRNA) signals consistently indicate PML risk and JCV reactivation across studies. Aim Here we synthesize and critically appraise evidence for miRNAs as biomarkers of PML risk and JCV activity in MS. Methods A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review of PubMed, Embase, Scopus, and Web of Science to April 1, 2025 identified studies assessing miRNAs and PML/JCV in MS. Two reviewers independently screened records and extracted data; findings were summarized qualitatively due to heterogeneity. Results Of 529 records screened, 7 studies met inclusion (n = 307 MS patients). The most consistent, previously elusive signals involved JCV miRNA-J1-5p and human miR-126, whose dysregulation recurred across independent cohorts and aligned with PML diagnosis or laboratory evidence of JCV reactivation. Across the included literature, miRNA profiling revealed add-on value to current JCV antibody and polymerase chain reaction (PCR)–based risk stratification, supporting its use as an adjunct rather than a replacement. Reporting was heterogeneous and effect estimates were seldom standardized, precluding meta-analysis. Conclusions Current evidence demonstrates a plausible, previously unresolved miRNA signature for PML risk and JCV activity, centered on JCV miRNA-J1-5p and miR-126. This synthesis opens the door to earlier, mechanism-informed surveillance and enables rational design of prospective validation studies for clinical translation.