CREB3L1 is a bZIP transcription factor normally anchored to endoplasmic reticulum membranes that undergoes proteolytic activation via regulated intramembrane proteolysis to function as a nuclear transcription factor 1. Physiologically, CREB3L1 regulates bone morphogenesis, neurogenesis, and secretory cell differentiation 1. During viral infection, CREB3L1 inhibits cell-cycle progression by activating transcription of cell-cycle inhibitors including p21/CDKN1A, thereby limiting virus spread 2. Pathologically, CREB3L1 drives cancer progression across multiple malignancies. In anaplastic thyroid carcinoma, CREB3L1 upregulation correlates with poor survival and promotes tumor growth and metastasis by activating extracellular matrix signaling and inducing cancer-associated fibroblasts through IL-1α production 3. In intrahepatic cholangiocarcinoma, CREB3L1 regulates S100P expression to promote tumor invasion 4. CREB3L1 also facilitates pancreatic ductal adenocarcinoma progression, promoting dense stroma formation via COL3A1 upregulation and reprogramming tumor-associated macrophages toward immunosuppressive M2 phenotype, resulting in reduced CD8+ T cell infiltration and immunotherapy resistance 5. In colorectal cancer, CREB3L1 regulates transformation of fibroblasts into THBS2-producing matrix CAFs 6. CREB3L1 serves as a master regulator of hepatic stellate cell activation during liver fibrosis 7. Clinically, CREB3L1 mutations cause osteogenesis imperfecta 1, and CREB3L1 gene fusions with EWSR1 characterize sclerosing epithelioid fibrosarcoma 8. CREB3L1 expression predicts immunotherapy resistance and poor prognosis in advanced cancers.