CRTC2 (CREB regulated transcription coactivator 2) serves as a key transcriptional coactivator that regulates hepatic glucose and lipid metabolism through multiple mechanisms 1. The protein functions by interacting with CREB to control gluconeogenic gene expression, with its activity regulated by phosphorylation-dependent nuclear-cytoplasmic shuttling 23. CRTC2 stabilization by Sam68 enhances gluconeogenesis, while proline hydroxylation by PHD3 at Pro129 and Pro615 residues is required for CREB association and nuclear translocation during fasting 23. Beyond glucose metabolism, CRTC2 regulates lipid homeostasis by competing with COPII complex components to control SREBP1 processing and transport, with mTOR-mediated phosphorylation modulating this inhibitory effect 4. Clinically, CRTC2 dysregulation contributes to metabolic diseases, with elevated expression in diabetes correlating with enhanced gluconeogenesis 23. In hepatocellular carcinoma, CRTC2 amplification promotes tumorigenesis by forming cytoplasmic condensates with YTHDF2, enhancing translation of m6A-modified mRNAs including LRP5 and c-Jun, and contributing to lenvatinib resistance 5. Additionally, CRTC2 regulates inflammatory responses in kidney injury through transcriptional activation of miR-93-3p, promoting macrophage polarization 6. These diverse functions position CRTC2 as a critical metabolic regulator and potential therapeutic target.