Circadian clock genes and insomnia: molecular mechanisms and therapeutic implications

Insomnia, affecting 30-40% of the global population, is a debilitating sleep disorder linked to significant health risks, including cardiovascular disease, metabolic syndrome, and neurodegeneration. Emerging evidence implicates dysregulation of circadian clock genes as a core molecular mechanism underlying its pathophysiology.

This review synthesizes current knowledge on how core clock genes regulate the sleep-wake cycle via transcription-translation feedback loops, incorporating recent insights into regulatory layers such as SUMOylation. We discuss how genetic polymorphisms and epigenetic modifications disrupt circadian rhythmicity, predisposing individuals to insomnia. The molecular pathways linking clock dysfunction to insomnia encompass dysregulation of neurotransmitter systems (melatonin, serotonin, GABA, dopamine), metabolic imbalance, neuroinflammation, mitochondrial oxidative stress, and altered synaptic plasticity. Chronic circadian misalignment, often driven by aberrant light exposure, exacerbates these disruptions.

Targeting circadian pathways presents novel therapeutic avenues. Melatonin receptor agonists facilitate sleep initiation and phase alignment; synthetic REV-ERBα/β ligands enhance circadian amplitude; dopaminergic modulators address hyperarousal; and GABAergic drugs restore inhibitory balance. Notably, Traditional Chinese Medicine formulations exhibit multi-pathway regulatory effects on clock gene expression. However, treatment efficacy varies across insomnia subtypes, and challenges regarding pharmacokinetics and long-term safety remain.

Dysfunctional circadian clock genes are pivotal in insomnia pathogenesis via interconnected molecular pathways. Future research should focus on biomarker-driven, personalized chronotherapies targeting these genes and their downstream effects to improve clinical outcomes.