CIDEB (cell death inducing DFFA like effector b) is a lipid droplet-associated protein that regulates hepatic lipid metabolism and represents a validated therapeutic target for metabolic liver disease. Primary Function: CIDEB promotes lipid storage and triacylglycerol-enriched VLDL particle formation in hepatocytes 1, while also regulating lipid droplet metabolism 2. Mechanism: Loss-of-function CIDEB mutations enhance hepatic fatty acid β-oxidation through ATGL and PPARα activation, concurrent with reduced hepatic lipogenesis 3. Cideb knockdown increases mitochondrial fat oxidation by ~25% and decreases plasma membrane diacylglycerol-PKCε signaling, which ameliorates insulin resistance 4. Disease Relevance: Rare germline loss-of-function variants in CIDEB confer substantial protection against liver disease, with 33% lower odds of any liver disease and 50% lower odds of cirrhosis 5. Somatic CIDEB mutations show positive selection in choline-deficient, high-fat diet-induced steatohepatitis but not all steatogenic contexts 3. Clinical Significance: Liver-specific CIDEB inhibition via siRNA ameliorates metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis in animal models, with improved metabolic profiles including reduced cholesterol, triglycerides, and hepatic steatosis 6. CIDEB inhibition represents a genetically-validated, promising therapeutic approach for MASLD 7.