DGAT2 is the acyltransferase catalyzing the terminal and rate-limiting step of triglyceride synthesis, converting diacylglycerol and fatty acyl-CoA into triacylglycerols 1. Localized to the endoplasmic reticulum, DGAT2 is essential for intracellular lipid storage and plays a central role in cytosolic lipid accumulation, particularly in hepatocytes where it incorporates endogenously synthesized fatty acids into triglycerides 1. Beyond triglyceride synthesis, DGAT2 functions as an acyl-CoA retinol acyltransferase and processes monoalkylglycerols for monoacylglycerol synthesis 2. DGAT2 has significant disease relevance in metabolic and neurodegenerative disorders. In nonalcoholic fatty liver disease (NAFLD), FXR agonists reduce hepatic lipid accumulation through DGAT2 repression independent of canonical lipogenic pathways 3. DGAT2 inhibition blocks SREBP-1 cleavage by redirecting diacylglycerol toward phosphatidylethanolamine synthesis, suppressing fatty acid synthesis and reducing hepatic steatosis 4. Loss-of-function variants in DGAT2 associate with lower plasma cholesterol and glucose levels, with selective DGAT2 inhibitors reducing fasting glucose and body weight in mice 5. In Alzheimer's disease pathology, microglial DGAT2 promotes lipid droplet formation upon amyloid-β exposure, impairing phagocytosis; DGAT2 inhibition restores microglial function and reduces amyloid burden 6. These findings establish DGAT2 as a multi-target therapeutic opportunity for metabolic and neurodegenerative diseases.