CREBL2 (cAMP responsive element binding protein like 2) is a transcription factor that functions as a regulator of cellular metabolism and differentiation. As a mammalian ortholog of Drosophila REPTOR-BP, CREBL2 mediates transcriptional responses downstream of mTORC1 signaling 1. In metabolic tissues, CREBL2 knockdown elevates glucose uptake, glycolysis, and triglyceride biosynthesis in muscle and liver cells, identifying it as a key metabolic regulator linking nutrient sensing to cellular metabolic responses 1. CREBL2 is directly phosphorylated by AMPK alongside other CREB family members, functioning downstream of energy-sensing pathways 2. In hepatic pathophysiology, PTH1R signaling upregulates CREBL2 in activated hepatic stellate cells, where it interacts with SMAD3 to increase TGF-β transcription and promote collagen deposition, thereby aggravating liver fibrosis 3. CREBL2 expression is negatively regulated by the oncogenic miR-17-92 cluster, suggesting tumor suppressive properties 4. Additionally, CREBL2 is located in chr12 regions frequently deleted in various cancers, supporting its potential role as a tumor suppressor 5. Aberrant CREBL2 function through fusion proteins (FUS-CREB3L2) in low-grade fibromyxoid sarcoma demonstrates its involvement in tumorigenesis via aberrant phase separation and ER stress pathways 6.