{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T08:17:04Z","timestamp":1788423424898,"version":"build-2803163510"},"reference-count":108,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100016350","name":"Sichuan Provincial Administration of Traditional Chinese Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100016350","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>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\u2014namely dopamine, adenosine, and glutamate\u2014ultimately 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.<\/jats:p>","DOI":"10.3389\/fnagi.2026.1942435","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T08:10:43Z","timestamp":1788423043000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multidimensional iron dysmetabolism and gut-brain axis interactions in restless legs syndrome: from peripheral deficiency to central dysregulation"],"prefix":"10.3389","volume":"18","author":[{"given":"Ziyang","family":"Liu","sequence":"first","affiliation":[{"name":"School of Sports Medicine and Health, Chengdu Sport University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunsong","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Sports Medicine and Health, Chengdu Sport University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yating","family":"Li","sequence":"additional","affiliation":[{"name":"School of Sports Medicine and Health, Chengdu Sport University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianbo","family":"Jia","sequence":"additional","affiliation":[{"name":"Gulin County Hospital of Traditional Chinese Medicine","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Cai","sequence":"additional","affiliation":[{"name":"School of Sports Medicine and Health, Chengdu Sport University","place":["Chengdu, China"]},{"name":"Sports Medicine Key Laboratory of Sichuan Province","place":["Chengdu, China"]},{"name":"Affiliated Sports Hospital of Chengdu Sport University","place":["Chengdu, China"]},{"name":"Institute of Sports Medicine and Health, Chengdu Sport University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1212\/WNL.0000000000001145","article-title":"MRI measurement of brain iron in patients with restless legs syndrome.","volume":"84","author":"Allen","year":"2015","journal-title":"Neurology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.sleep.2017.11.1126","article-title":"Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome\/Willis-Ekbom disease in adults and children: An IRLSSG task force report.","volume":"41","author":"Allen","year":"2018","journal-title":"Sleep Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/s1389-9457(03)00010-8","article-title":"Restless legs syndrome: Diagnostic criteria, special considerations, and epidemiology. 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