Fatty acid synthase (FASN) (FASN)

Fatty acid synthase (FASN) is a complex, multi-domain homodimeric enzyme that plays a central role in de novo lipogenesis by converting acetyl-CoA and malonyl-CoA into long-chain fatty acids, primarily palmitate (UniProt P49327). While most adult human tissues satisfy their lipid requirements through the uptake of exogenous dietary fats, FASN is frequently overexpressed in a wide variety of cancers (Menendez & Lupu, 2007, Nature Reviews Cancer). In these malignant cells, FASN supports the increased demand for membrane phospholipids and signaling molecules required for rapid cell proliferation. Consequently, FASN has emerged as a significant therapeutic target in oncology, with inhibition leading to decreased tumor growth and induction of apoptosis. Additionally, FASN is a key driver in metabolic diseases such as non-alcoholic steatohepatitis (NASH), where its upregulation in the liver leads to excessive fat accumulation and inflammation (Loomba et al., 2021, Journal of Hepatology). Clinical-stage inhibitors like denifanstat (TVB-2640) have demonstrated the ability to reduce hepatic fat content and improve fibrosis markers in patients with NASH (ClinicalTrials.gov NCT04766424). Therapeutic development faces challenges regarding safety, as FASN inhibition can affect sebum production in the skin and tear film in the eyes, leading to side effects such as dry skin and ocular irritation.

Other names

FASSDR27X1Short chain dehydrogenase/reductase family 27X member 1OA-519Short-chain-enoyl-CoA hydratase

Inhibition of the fatty acid synthase enzyme complex, specifically targeting the beta-ketoacyl synthase (KS) domain or other catalytic sites to block the de novo synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA.