Repurposing a tricyclic antidepressant in tumor and metabolism disease treatment through fatty acid uptake inhibition

• DOI: 10.1084/jem.20221316
• Publication Date: 2022-12-15T15:03:33Z
• Authors: Qiaoyun Chu; Jing An; Ping Liu; Yihan Song; Xuewei Zhai; Ronghui Yang; Jing Niu; Chuanzhen Yang; Binghui Li
• Keywords: Lipogenesis; Steatosis; Fatty Acid Metabolism

Fatty acid uptake is essential for cell physiological function, but detailed mechanisms remain unclear. Here, we generated an acetyl-CoA carboxylases (ACC1/2) double-knockout line, which lacked fatty biosynthesis and survived on serum acids was used to screen inhibitors. We identified a Food Drug Administration–approved tricyclic antidepressant, nortriptyline, that potently blocked both in vitro vivo. also characterized underlying whereby nortriptyline provoked lysosomes release protons induce acidification suppress macropinocytosis, accounted endocytosis. Furthermore, alone or combination with ND-646, selective ACC1/2 inhibitor, significantly repressed tumor growth, lipogenesis, hepatic steatosis mice. Therefore, show cells actively take up through provide potential strategy suppressing controlling the cellular level of acids.