Sleep and circadian disturbances (SCRD) both contribute to and result from endoplasmic reticulum (ER) stress, which triggers the unfolded protein response (UPR) via ATF6, PERK, and IRE1 to restore proteostasis. Because persistent ER stress can worsen SCRD and related pathology, UPR modulation is a potential therapeutic strategy. Here, we examine casein kinase 1 (CK1) δ/ε as a regulator of circadian rhythms and ER stress signalling. Using U2OS and SH-SY5Y cells, we tested pharmacological inhibition of CK1 across UPR branches. In mice, we assessed circadian phase and sleep architecture under baseline conditions and following induced SCRD, measured ER stress markers in the brain and peripheral tissues, and evaluated cognition with tests of spatial memory and executive function. CK1 inhibition tuned UPR signalling in vitro and in vivo, modulated sleep and circadian parameters, and produced tissue-specific changes in ER stress markers. Importantly, CK1 inhibition mitigated SCRD-associated cognitive deficits, correlating with reduced ER stress markers in learning- and memory-related brain regions. Together, these data identify CK1 as a promising therapeutic target linking circadian regulation, sleep homeostasis, and cellular stress resilience.
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