CREB3L2 is a transmembrane transcription factor that plays critical roles in the unfolded protein response (UPR) and cellular stress adaptation. Under normal conditions, CREB3L2 resides in the endoplasmic reticulum (ER) membrane with its DNA-binding domain facing the cytoplasm 1. Upon ER stress, it undergoes regulated intramembrane proteolysis and translocates to the nucleus to activate target gene transcription. CREB3L2 demonstrates significant pathological relevance through chr7 translocations, particularly the FUS-CREB3L2 fusion in low-grade fibromyxoid sarcoma (LGFMS), which drives tumorigenesis by aberrant phase separation and remodeling of ER membranes 1. This fusion protein activates hundreds of LGFMS-specific genes including CD24 and MUC4 2. In hepatocellular carcinoma, CREB3L2 promotes tumor progression and lenvatinib resistance by upregulating SREBP1-mediated lipid metabolism through HAT1-dependent mechanisms 3. Additionally, CREB3L2 forms heterodimers with ATF4 in neurons, contributing to transcriptional dysregulation in Alzheimer's disease pathology, where proteasome inhibition by Aβ42 increases CREB3L2 levels 4. These diverse functions highlight CREB3L2's importance in both normal cellular homeostasis and disease pathogenesis.