Emerging mechanisms in restless legs syndrome: Revisiting pathophysiology over the past 10 years

Restless legs syndrome (RLS) is a neurologic disorder characterized by an irresistible urge to move the legs, typically worsening during periods of rest and at night. The disorder significantly impairs sleep and quality of life. Despite available pharmacologic options, many patients experience suboptimal long-term control, likely reflecting an incomplete understanding of RLS mechanisms. A literature review was performed using PubMed, Scopus, and Google Scholar. Publications from 2015 to 2025 were screened, prioritizing landmark clinical trials, neuroimaging studies, and mechanistic investigations. Data were synthesized to identify consistent and emerging themes in RLS pathophysiology. The most consistently supported mechanisms involve dopaminergic dysfunction, altered striatal dopamine receptor activity, abnormalities in brain iron metabolism, and hyperglutamatergic state linked to hypoadenosine dysfunction. Genetic susceptibility and circadian modulation also appear to contribute to disease expression. Recent evidence suggests a novel role for hypo-adenosine signaling, potentially linking dopaminergic and iron pathways through adenosine modulation. Over the past decade, neuroimaging and molecular research advances have expanded understanding of RLS pathophysiology beyond traditional dopamine and iron models. The emerging hypo-adenosine hypothesis may offer a unifying framework to explain variability in treatment response and disease progression. Future research integrating these pathways could guide the development of more targeted and durable therapies. This narrative review synthesizes findings from the past ten years to examine how current models of restless legs syndrome pathophysiology have evolved, why key mechanistic findings remain inconsistent, and which gaps warrant priority in future investigation.