CRTC1 is a transcriptional coactivator that functions as a key regulator of CREB-mediated gene expression across multiple physiological and pathological contexts. Mechanistically, CRTC1 binds to CREB and activates transcription of target genes involved in neuronal plasticity, circadian rhythm regulation, and cellular stress responses 12. In normal physiology, CRTC1 regulates circadian entrainment by integrating adenosine-derived sleep signals with light through Ca2+-ERK-AP-1 and CREB/CRTC1-CRE pathways to control clock genes Per1 and Per2 1. CRTC1 also plays critical roles in asthma pathogenesis, where eosinophil extracellular traps activate pulmonary neuroendocrine cells via the CCDC25-ILK-PKCα-CRTC1 pathway, amplifying allergic immune responses 3. Clinically, CRTC1 is implicated in multiple malignancies. CRTC1-MAML2 fusion, characteristic of mucoepidermoid carcinomas, constitutively activates CREB-mediated transcription to promote cell growth and survival 4. CRTC1::TRIM11 fusions define an emerging cutaneous melanocytic tumor entity with potential for metastasis 5. In Alzheimer's disease, CRTC1 dysregulation occurs through reduced DNA methylation in hippocampal promoter regions 6 and S-nitrosylation at Cys216, which impairs CREB binding and disrupts activity-dependent gene expression critical for synaptic plasticity and memory 2.