Multidimensional iron dysmetabolism and gut-brain axis interactions in restless legs syndrome: from peripheral...

Restless Legs Syndrome (RLS) is a sensorimotor neurological disorder characterized by an irresistible urge to move the lower limbs. Although traditional paradigms attribute its pathogenesis to peripheral iron deficiency, many clinically diagnosed patients present with normal peripheral iron indicators yet exhibit central iron homeostatic dysregulation. This discrepancy highlights a distinct decoupling between peripheral iron stores and central iron availability. The RLS-associated iron metabolic impairment is inherently a complex pathological network orchestrated by multidimensional processes, including intestinal absorption, systemic distribution, blood-brain barrier (BBB) transport, and intracellular utilization. Crucially, gut dysbiosis-induced low-grade enterogenous inflammation may activate the IL-6/hepcidin pathway, thereby sequestering systemically available iron; this mechanism represents a pivotal upstream driver of central iron insufficiency. Consequently, impaired cerebral iron utilization disrupts the physiological equilibrium of neurotransmitter systems-namely dopamine, adenosine, and glutamate-ultimately triggering the sensorimotor symptoms and sleep disturbances characteristic of RLS. Therefore, clinical management should shift away from relying solely on isolated peripheral indicators toward implementing individualized iron supplementation phenotyped by specific absorption, distribution, or transport mechanisms. Looking forward, microecological interventions utilizing prebiotics or short-chain fatty acids (SCFAs) to mitigate systemic inflammation and ameliorate the intestinal environment hold substantial promise as a synergistic therapeutic strategy for RLS.