CRY1 is a core circadian clock gene encoding a transcriptional repressor that helps regulate the ~24-hour rhythms controlling sleep, metabolism, and numerous physiological processes. CRY1 forms part of the negative feedback loop of the circadian clock by repressing the transcriptional activity of CLOCK-BMAL1, which otherwise activate clock-controlled genes. CRY1 is more potent than its homolog CRY2 as a transcriptional repressor in cerebellum and liver, and is more effective at lengthening circadian oscillator periods. Beyond circadian functions, CRY1 regulates metabolic processes including hepatic gluconeogenesis and glucose-lipid metabolism, influences immune tolerance in macrophages, and modulates granulosa cell senescence through ferritinophagy. A dominantly inherited CRY1 variant causing gain-of-function (enhanced binding to CLOCK and BMAL1) was identified in familial delayed sleep phase disorder, with the allele present in up to 0.6% of the population and associated with late or fragmented sleep in carriers 1. Disease associations include delayed sleep phase syndrome, cluster headache (linked to the rs8192440 variant with stronger association in patients reporting diurnal attack rhythmicity) 2, and circadian disruption-related conditions including obesity and obesity-related cancers 3. Recent evidence suggests CRY1 stabilizers may enhance ovarian function in aged mice 4, while butyrate supplementation upregulates CRY1 expression and improves inflammation and sleep quality in active ulcerative colitis patients 5.