Serum Biomarkers in Restless Legs Syndrome: Beyond the Classical Iron Paradigm-A Scoping Review

Restless legs syndrome (RLS) is one of the most prevalent sleep disorders, yet its diagnosis continues to rely almost entirely on subjective symptom descriptions. This persistent dependence on phenomenology reflects the absence of reliable biological markers to aid in the process of diagnosis or monitoring. However, there is accumulating molecular evidence that suggests that RLS is associated with systemic biological alterations. These extend beyond the traditional paradigm of iron deficiency. The present scoping review synthesizes the current research on circulating serum biomarkers investigated in RLS outside classical iron indices. A comprehensive search of PubMed, Scopus, and Web of Science databases identified 1050 records, of which 50 studies met eligibility criteria and were included. In the processing of data, clusters emerged into several recurring biological domains, including dysregulated iron regulatory signaling (hepcidin), low-grade immune activation, oxidative stress, and neuroaxonal injury markers. High-throughput omics studies reveal molecular network perturbations involving inflammatory pathways, complement activation, metabolic signaling, and cellular stress responses. Biomarker associations appear stronger when linked to objective motor burden. These findings suggest that RLS may involve multifarious molecular changes detectable in the serum. Consequently, this can support the transition from symptom-based diagnosis toward biomarker-informed stratification, which may enable more precise disease characterization and improved diagnostic accuracy.