CREB3L3 is a transcription factor that primarily regulates hepatic lipid metabolism and maintains normal plasma triglyceride concentrations 1. As a member of the CREB3 family, CREB3L3 is activated during endoplasmic reticulum stress through regulated intramembrane proteolysis and responds to cAMP stimulation by binding cAMP response elements (CRE) and box-B elements to activate target gene transcription 2. In the liver, CREB3L3 works synergistically with PPARα to regulate fatty acid oxidation and ketogenesis during fasting, with distinct but complementary roles: CREB3L3 primarily controls apolipoprotein metabolism while PPARα governs intracellular lipid metabolism 3. CREB3L3 also regulates FGF21 transcription as part of a CREBH-FGF21 signaling axis that reduces hepatic steatosis 4. Beyond hepatic function, CREB3L3 is expressed in adipose tissue where it modulates body weight and metabolic health; its adipose-specific overexpression reduces diet-induced obesity and improves insulin sensitivity 5. Clinically, CREB3L3 mutations are associated with hypertriglyceridemia type 2 1. Additionally, CREB3L3 fusions with EWSR1 occur in sclerosing epithelioid fibrosarcoma and rare intracranial mesenchymal tumors 67.