It’s widely accepted that the local brain iron level plays an important role in RLS pathophysiology, however, the mechanism is still unclear. Recent studies demonstrated that the iron deficiency in brain was related to the function of blood-brain interface, as BBBs endothelial cells acted as an iron reservoir for the brain. A dysfunction of iron regulatory protein in the microvasculature incited dysregulation of iron transport across the BBB, resulting in a decrease of iron storage in endothelial cells (Lee et al., 2001). Biochemical studies on the effect of iron in brain indicated that several proteins containing iron were included in various processes like oxidative phosphorylation, oxygen transportation, myelin production and the synthesis and metabolism of neurotransmitters (Ward et al., 2014). Therefore, iron deficiency can lead to cellular damage by oxidation and modification of cellular compounds such as lipids, carbohydrates, protein, and DNA from hydroxyl radical production (Ward et al., 2014). The interactions between impaired neuronal iron uptake and the functions of the neuromelanin-containing and dopamine-producing cells play important roles in RLS pathophysiology (Michaud et al., 2004). Decreased extracellular dopamine, DAT, D1 and D2 receptors are found in iron deficiency, indicating that iron affect the brain dopaminergic transmission in different ways (Dauvilliers and Winkelmann, 2013).