DGAT2: A key therapeutic target in lipid synthesis regulation and metabolic diseases

Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final committed step in the intracellular triglyceride (TG) synthesis pathway. It plays a critical role in energy metabolism by catalyzing the esterification of diacylglycerol (DG) into TG for storage. DGAT2 differs significantly from DGAT1-an unrelated enzyme from a distinct gene family that catalyzes the same biochemical reaction-in terms of structure, expression, and function. While DGAT2 is essential for skin barrier integrity (whose global absence is lethal in mice), its role in intracellular lipid storage in other tissues can often be compensated for by DGAT1. The expression and activity of DGAT2 are subject to complex multilevel regulation, including transcriptional control and post-translational modifications. Dysregulation of DGAT2 is a critical factor in the pathogenesis of several metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D). Given its substantial pathophysiological significance, DGAT2 has emerged as a key therapeutic target for metabolic diseases. Current therapeutic strategies include small-molecule inhibitors that directly suppress the enzyme activity of DGAT2, as well as nucleic acid-based approaches that silence DGAT2 mRNA expression. Here, we highlight the physiological and pathological roles of DGAT2, as well as the current therapeutic strategies targeting DGAT2 for the treatment of metabolic disorders.