The PER Gene Family: Pivotal Regulators Bridging Circadian Clock Disruption to Multifactorial Pathologies

The Period genes, PER1, PER2, and PER3, encode core negative regulators of the mammalian circadian clock and provide an important link between circadian disruption and chronic disease states. Although they belong to the same gene family, PER1, PER2 and PER3 show partially distinct roles in environmental entrainment, feedback-loop stability, sleep homeostasis, and disease susceptibility. Beyond maintaining circadian rhythmicity, PER proteins participate in cellular processes relevant to chronic disease, including metabolic regulation, immune responses, cell-cycle control, DNA-damage responses, and treatment sensitivity. Clinically, PER dysregulation has been associated with circadian rhythm sleep disorders, cancer, neurodegenerative and psychiatric disorders, cardiovascular dysfunction, and chronic inflammation. The strength of evidence varies across disease contexts. Defined PER2-related alterations provide relatively strong causal evidence in selected sleep-phase disorders, whereas PER abnormalities in most cancers and complex chronic diseases are mainly associative, prognostic, or preclinical. In cancer, PER dysregulation frequently involves altered expression, promoter methylation, disrupted rhythmicity or genetic variation, with potential relevance to prognosis and treatment response. Current circadian-based strategies, including behavioural entrainment, treatment timing, supportive circadian regulation, and pharmacological clock modulation, remain at different stages of clinical maturity. Overall, the PER axis should be viewed as a context-dependent clinical modifier and biomarker candidate rather than a universal disease driver, with future value in risk stratification and chronotherapy-oriented research.