The stress response is essential for cellular and organismal survival as it acts as a protective and adaptive mechanism to maintain homeostasis. At the organismal level, physical stressors induce responses in mammals that are mediated primarily by the hypothalamic-pituitary-adrenal (HPA) axis, which regulates glucocorticoid secretion. The HPA axis functions as a circadian-regulated, multi-oscillator system, in which the paraventricular nucleus, the pituitary, and the adrenal gland exhibit intrinsic rhythmicity while remaining coordinated by the output from the suprachiasmatic nucleus. Glucocorticoids act both as stress effectors and systemic zeitgebers that synchronize peripheral clocks. At the cellular level, cellular stressors are sensed by four protein kinases of eukaryotic translation initiation factor 2α (eIF2α) and activate the evolutionarily conserved integrated stress response (ISR), which converges on phosphorylation of Serine 51 on eIF2α. ISR signaling is temporally regulated by the circadian clock and controls time-of-day-dependent protein synthesis. In parallel, ISR pathways feed back onto the circadian clock through transcriptional, translational and epigenetic mechanisms, directly influencing core clock gene expression and stability of circadian oscillations. Physiological ISR activity supports circadian robustness and resetting, whereas excessive ISR activation dampens rhythmic gene expression and destabilizes behavioral rhythms. The current review summarizes recent advances in our understanding of the crosstalk mechanisms between the HPA axis, ISR, and the circadian clock to provide new insights into disease mechanisms and inform chronotherapeutic strategies to target dysregulated HPA and ISR activities and restore temporal homeostasis.
