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

Chu et al. identify a clinical drug, nortriptyline that can potently inhibit macropinocytosis-mediated fatty acid uptake, and further find that nortriptyline effectively suppresses tumor growth, lipogenesis, and hepatic steatosis in combination with ND-646, a selective ACC1/2 inhibitor. 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 cell line, which lacked fatty acid biosynthesis and survived on serum fatty acids and was used to screen for fatty acid uptake inhibitors. We identified a Food and Drug Administration-approved tricyclic antidepressant, nortriptyline, that potently blocked fatty acid uptake both in vitro and in vivo. We also characterized underlying mechanisms whereby nortriptyline provoked lysosomes to release protons and induce cell acidification to suppress macropinocytosis, which accounted for fatty acid endocytosis. Furthermore, nortriptyline alone or in combination with ND-646, a selective ACC1/2 inhibitor, significantly repressed tumor growth, lipogenesis, and hepatic steatosis in mice. Therefore, we show that cells actively take up fatty acids through macropinocytosis, and we provide a potential strategy suppressing tumor growth, lipogenesis, and hepatic steatosis through controlling the cellular level of fatty acids.

Automated summary

The study identifies nortriptyline as a drug that can inhibit fatty acid uptake in cells and effectively suppress tumor growth, lipogenesis, and hepatic steatosis. The researchers also provide insights into the mechanisms through which nortriptyline blocks fatty acid uptake and suggest a potential strategy for controlling fatty acid levels to inhibit tumor growth and metabolic disorders.