PER2 (period circadian regulator 2) is a transcriptional repressor and core component of the molecular circadian clock that generates approximately 24-hour rhythms in gene expression. As a negative limb of the transcription/translation feedback loop, PER2 interacts with the CLOCK-BMAL1 heterodimer to inhibit its activity and regulate circadian-controlled genes through multiple mechanisms, including chr2 remodeling via SIN3-HDAC complexes and H3K9 methyltransferase recruitment [UniProt annotation]. PER2 regulates diverse physiological processes including metabolism, sleep, cardiovascular function, and immune responses 1. Beyond canonical clock function, PER2 has emerged as a critical regulator of cellular pathways relevant to human disease. In oral squamous cell carcinoma, PER2 suppresses PD-L1 expression through IKK/NF-κB pathway inhibition via HSP90 binding, enhancing anti-tumor immune responses 2. PER2 also promotes cuproptosis in OSCC cells through HSP70 interaction-mediated AKT degradation 3. In pituitary tumorigenesis, PER2 upregulation accelerates adenoma growth by enhancing HIF-1α-dependent transcription of cell cycle genes 4. Conversely, NAD+ supplementation via nicotinamide riboside restores PER2 function in aging through K680 deacetylation, enhancing circadian oscillations and metabolic rhythms 5. Urolithin A similarly amplifies circadian amplitude by destabilizing PER2 while stabilizing SIRT1 6. A heterozygous BMAL1 variant study revealed that disrupted PER2 mRNA cycling associates with developmental delay and autism spectrum disorder, highlighting neurodevelopmental roles beyond canonical circadian function 7.