Beyond the biological clock: circadian control of cellular stress pathways and implications for chronomedicine

Circadian rhythms are traditionally understood as regulators of sleep – wake timing, metabolism, and hormonal cycles. However, emerging evidence reveals that circadian regulation extends beyond classical physiological processes to encompass cellular stress pathways and proteostatic mechanisms previously considered largely independent of circadian control. This review presents current knowledge on four key noncanonical circadian targets – the unfolded protein response (UPR), oxidative stress regulation via the Nrf2/Keap1 pathway, autophagy-mediated quality control, and oxytocin-driven neuroendocrine signalling. Each of these systems displays intrinsic rhythmicity and, in turn, feeds back onto core clock machinery, forming bidirectional regulatory loops. We further highlight how circadian misalignment exacerbates ER stress, ROS accumulation, proteostasis failure, and neuroendocrine imbalance, contributing to the pathogenesis of metabolic disorders, neurodegeneration, inflammation, and stress-related disease. Integrative omics and systems biology approaches now reveal that these pathways operate not as isolated modules but as a unified temporal network orchestrated by the clock. Recognizing these underappreciated circadian dimensions opens new therapeutic avenues, suggesting that pharmacological or behavioural interventions targeting stress response pathways may gain efficacy when aligned with biological time. This expanded framework positions circadian regulation as a central coordinator of cellular resilience and a promising entry point for precision chronotherapy.