To review the influence of circadian rhythmicity on cerebral vulnerability and the time-dependent efficacy of current neurotherapeutic interventions.

We performed a PRISMA-guided systematic review across PubMed, Scopus, and Web of Science examining stroke incidence, severity, mechanisms, and time-dependent interventions, with secondary goals of circadian factors in wake-up stroke management.

 Late-night/early-morning onset correlates with up to 23% ischemic stroke outcomes, characterised by increased deficit and poor three-month recovery (p=0.03). Injury is time-dependent, linked to circadian control involving neuroprotection by agents (αPBN, MK-801),  ROR\alpha for melatonin-mediated reperfusion protection, Bmal1-driven angiogenesis, and Smyd-2-regulated cell death. Low cerebrospinal fluid Hypocretin-1 (Hcrt-1) levels were identified as an independent predictor of poor post-stroke sleep quality, significantly improving prediction model performance (AUC increase to 0.857). Preclinical studies reported infarct volume to be 28% larger than resting period in animals. These findings confirm stroke is a time-sensitive pathology governed by systemic and cellular clocks (e.g., astrocyte-clocks). Integrating an individual’s internal chronotype is paramount for optimizing the therapeutic window, particularly when guiding advanced reperfusion selection via imaging criteria (e.g., DWI-FLAIR mismatch).

Circadian biology is a critical, actionable factor of stroke pathophysiology. Our findings suggest integrating patient-specific chronotype assessment, diagnostic assessments (e.g., Hcrt-1), and circulating biomarkers is crucial for precision chronotherapy, enabling personalized treatments that improve neuroprotection and thereby maximizing functional neurological outcomes.