Circadian rhythms and non-coding RNAs: mechanistic insights, clinical impact, and future opportunities for personalized medicine

Circadian rhythms are intrinsic 24-hour cycles that regulate diverse physiological processes, including sleep-wake cycles, metabolism, immune function, and hormone secretion. The molecular clockwork is made up of regulatory feedback loops and core clock genes governs these cycles. These rhythms confer adaptive advantages by enabling organisms to anticipate predictable environmental cycles such as light-dark transitions, nutrient availability, and temperature fluctuations, thereby optimizing energy utilization and survival. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have become important regulators of circadian rhythms on several levels as they alter clock gene transcription. This review provides a comprehensive overview of ncRNAs in circadian regulation, highlighting specific miRNAs that modulate clock genes, as well as lncRNAs that act as scaffolds, sponges, or transcriptional regulators to fine-tune circadian oscillations. Circadian misalignment caused by genetic, environmental, or lifestyle factors disrupts ncRNA expression and has been linked to cancer, cardiovascular disorders, autoimmune conditions, gastrointestinal dysfunction, neurological and psychiatric diseases, and respiratory illnesses. The clinical potential of circulating miRNAs as biomarkers for circadian disruption and the therapeutic approaches targeting ncRNAs to restore circadian balance were discussed, alongside emerging strategies in precision medicine to incorporate interindividual variability into treatment design. Finally, the present review outlined the current challenges and future perspectives to allow better understanding of the ncRNA-circadian interactions, to translate findings into clinical intervention, and to underscore the importance of ncRNAs as both regulators and therapeutic targets in circadian biology and human disease.