Non-coding RNAs in circadian network regulation and disease: from oscillatory coupling to precision chronomedicine

Circadian rhythms are sustained by a hierarchically organized transcription–translation feedback loop (TTFL) that coordinates physiological processes across tissues. Emerging evidence indicates that non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, are integral components of this oscillatory system. Rather than functioning solely as downstream regulators, ncRNAs modulate core clock genes, mediate environmental entrainment, and couple central and peripheral oscillators to tissue-specific outputs. Disruption of ncRNA–clock interactions destabilizes oscillatory amplitude, alters phase coherence, and weakens network robustness, thereby contributing to metabolic disorders, neuropsychiatric diseases, inflammatory conditions, and tumor progression. Increasing experimental evidence from inducible genetic models and functional rescue studies supports a causal role for specific ncRNAs in circadian network destabilization rather than mere association. Beyond local regulation, circulating and exosomal ncRNAs may act as systemic time signals that coordinate inter-organ communication. This systems-level perspective reframes circadian dysfunction as a network instability state in which feedback perturbations propagate across hierarchical clock layers. Future progress will require temporally resolved multi-omics approaches, tissue-specific perturbation models, and chronotherapeutic strategies aimed at restoring oscillatory amplitude and synchronization. Integrating ncRNA biology with circadian systems modeling may facilitate precision chronomedicine and help determine whether temporal architecture can serve as a modifiable therapeutic target.