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REVIEW article

Front. Neurosci.

Sec. Neuroendocrine Science

Volume 19 - 2025 | doi: 10.3389/fnins.2025.1638270

This article is part of the Research TopicNeuromodulation of mood and eating behaviorView all 6 articles

Hypocretin: a promising target for the regulation of homeostasis

Provisionally accepted
Yutong  WangYutong Wang1,2Su  FuSu Fu1Jian  MaoJian Mao2*Kun  CuiKun Cui2*Hong  JiangHong Jiang1,2*
  • 1Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China
  • 2Beijing Life Science Academy, Beijing, China

The final, formatted version of the article will be published soon.

Hypocretin, also known as orexin, is a hypothalamic neuropeptide that regulates essential physiological processes including arousal, energy metabolism, feeding behavior, and emotional states. Through widespread projections and two G-protein-coupled receptors—HCRT-1R and HCRT-2R—the hypocretin system exerts diverse modulatory effects across the central nervous system.The role of hypocretin in maintaining wakefulness is well established, particularly in narcolepsy type 1 (NT1), where loss of hypocretin neurons leads to excessive daytime sleepiness and cataplexy. However, the mechanisms by which hypocretin stabilizes transitions between sleep stages remain incompletely understood. Additionally, while hypocretin integrates metabolic signals such as glucose, leptin, and ghrelin to promote feeding and energy expenditure, NT1 patients paradoxically experience weight gain despite reduced caloric intake—highlighting unresolved questions about hypocretin’s role in energy homeostasis.In the affective domain, preclinical studies suggest hypocretin enhances stress resilience and modulates anxiety- and depression-related behaviors. Yet, human data remain inconsistent, in part due to methodological variability and the limited availability of cerebrospinal fluid sampling to accurately assess central hypocretin function.Therapeutically, the hypocretin system is a promising target across several domains. Dual hypocretin receptor antagonists (DORAs), such as suvorexant and daridorexant, are clinically approved for insomnia. Selective HCRT-2R agonists—including TAK-861 and ALKS-2680—are in clinical trials for NT1 and show encouraging results. Additionally, HCRT-2R antagonists like seltorexant are being explored for major depressive disorder.This review will highlight the anatomical distribution, receptor mechanisms, and physiological functions of the hypocretin system. It will also focus to discuss its role in narcolepsy, metabolic regulation, and mood disorders, while addressing key challenges and open questions that must be resolved to fully harness hypocretin’s therapeutic potential

Keywords: Hypocretin (orexin), Sleep, Wakefulness, Metabolism, Mood Disorders, Narcolepsy

Received: 30 May 2025; Accepted: 08 Aug 2025.

Copyright: © 2025 Wang, Fu, Mao, Cui and Jiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Jian Mao, Beijing Life Science Academy, Beijing, China
Kun Cui, Beijing Life Science Academy, Beijing, China
Hong Jiang, Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China

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