Fatty acid synthase (FASN)

Class

Small-molecule FASN inhibitor

Pathway

De novo lipogenesis — blocks the terminal enzyme synthesizing palmitate, reducing hepatic lipotoxic lipid accumulation

Fatty acid synthase (FASN) is the multidomain enzyme that carries out the final, committed step of de novo lipogenesis: it condenses acetyl-CoA and malonyl-CoA, using NADPH as a reducing cofactor, to produce palmitate, the precursor for most cellular fatty acids. In the liver, when carbohydrate intake is high, transcription factors such as SREBP-1c strongly upregulate FASN, driving continuous fat synthesis even when the liver already stores excess lipid. This overproduction contributes to accumulation of triglycerides and lipotoxic byproducts inside hepatocytes, a process implicated in fatty liver disease and its progression to inflammation and fibrosis. Small-molecule FASN inhibitors aim to reduce this de novo fat production, thereby lowering the flux of new, potentially harmful lipid species entering hepatocytes. Beyond metabolic liver disease, FASN is also upregulated in certain rapidly proliferating tissues and tumors that depend on self-made lipid for membrane construction and energy storage, making the enzyme a mechanism of interest across both metabolic and oncologic contexts. Because FASN activity is tied closely to whole-body lipid handling, modulating it has consequences that extend beyond the liver, including in tissues where sebum and lipid-rich skin barrier components are made.