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Circadian–immune crosstalk in insomnia disorder: mechanisms and therapeutic implications
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DOI：10.3389/fnins.2026.1881195.png)
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Abstract
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Insomnia disorder (ID) is a common sleep–wake disorder characterized by persistent difficulty initiating or maintaining sleep; early-morning awakening; or non-restorative sleep; accompanied by daytime functional impairment. ID has traditionally been explained by the hyperarousal model; which emphasizes cognitive; emotional; cortical; neuroendocrine; and autonomic overactivation. However; this model alone does not fully account for the chronic persistence; relapse tendency; and multisystem associations of ID. Emerging evidence suggests that circadian rhythm disruption; impaired melatonin signaling; hypothalamic–pituitary–adrenal (HPA) axis activation; autonomic imbalance; and low-grade inflammation may also contribute to the development and maintenance of ID. Available evidence indicates that sleep disturbance is more consistently associated with selected inflammatory markers; particularly C-reactive protein (CRP) and interleukin-6 (IL-6); whereas findings for tumor necrosis factor-alpha (TNF-α) remain less consistent. The circadian system regulates sleep; endocrine function; metabolism; and immune-inflammatory activity through the suprachiasmatic nucleus; melatonin and cortisol rhythms; peripheral clock genes; and rhythmic immune-cell responses. Disruption of this temporal network may alter melatonin secretion; inflammatory rhythmicity; and stress-related neuroendocrine responses; thereby contributing to the persistence of insomnia symptoms. Compared with previous reviews that have separately discussed hyperarousal; circadian rhythm disruption; melatonin signaling; or sleep-related inflammation; this review integrates these processes into a circadian–immune perspective for understanding ID. We summarize alterations in sleep–wake rhythms; melatonin signaling; HPA-axis activity; autonomic regulation; and immune-inflammatory responses in ID; and discuss potential intervention strategies; including light management; melatonin and melatonin receptor agonists; cognitive behavioral therapy for insomnia (CBT-I); physical activity; time-restricted eating; and stress management. This review aims to provide a mechanistic basis for understanding the chronicity and heterogeneity of ID and for developing individualized intervention strategies.
Keywords:
melatonin
circadian rhythm
immune inflammation
insomnia disorder
low-grade inflammation
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