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While pharmacological therapies have evolved to mitigate symptoms, they fail to address the core pathology\u2014orexin deficiency. This narrative review examines the potential of orexin cell transplantation as an innovative therapeutic approach to restore orexin signalling and treat the root cause of narcolepsy. We begin by examining the clinical features, pathophysiology, and diagnostic criteria of narcolepsy, focusing on the essential role of orexins in regulating the sleep\u2013wake cycle and the neurobiological mechanisms underlying cataplexy. The review then explores experimental therapeutic approaches, including hypothalamic tissue grafts, gene therapy, and immortalised orexin\u2010expressing cell lines, highlighting their potential to address the orexin deficit in narcolepsy. While preclinical studies show that transplanted orexin cells can integrate into host neural networks, enhance sleep stability, and decrease the frequency of cataplexy in animal models, several challenges remain. Immortalised orexin cell lines offer a scalable and consistent option for transplantation therapies. However, immune rejection, long\u2010term cell survival, and complete functional integration persist. These translational hurdles must be addressed to bring these therapies to clinical practice. This review underscores the need for continued research to overcome these barriers and optimise cell\u2010based therapies for narcolepsy.<\/jats:p>","DOI":"10.1111\/jsr.70083","type":"journal-article","created":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T01:24:31Z","timestamp":1746494671000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Orexin Restoration in Narcolepsy: Breakthroughs in Cellular Therapy"],"prefix":"10.1111","volume":"35","author":[{"given":"Emmanuel","family":"Ortega\u2010Robles","sequence":"first","affiliation":[{"name":"Unidad de Trastornos del Movimiento y Sue\u00f1o (TMS) Hospital General Dr. Manuel Gea Gonz\u00e1lez  Ciudad de M\u00e9xico Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Guerra\u2010Crespo","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Laboratorio de Medicina 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