Nucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet.

The synthesis of fatty acids from acetyl-coenzyme A (AcCoA) is deregulated in diverse pathologies, including cancer. Here, we report that fatty acid accumulation is negatively regulated by nucleoside diphosphate kinases 1 and 2 (NME1/2), housekeeping enzymes involved in nucleotide homeostasis that were recently found to bind CoA. We show that NME1 additionally binds AcCoA and that ligand recognition involves a unique binding mode dependent on the CoA/AcCoA 3' phosphate.

GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma modulation of lysosomal functions.

Hepatocellular carcinoma is the most frequent primary liver cancer. Macroautophagy/autophagy inhibitors have been extensively studied in cancer but, to date, none has reached efficacy in clinical trials. In this study, we demonstrated that GNS561, a new autophagy inhibitor, whose anticancer activity was previously linked to lysosomal cell death, displayed high liver tropism and potent antitumor activity against a panel of human cancer cell lines and in two hepatocellular carcinoma in vivo models.

Modeling Diet-Induced NAFLD and NASH in Rats: A Comprehensive Review.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, characterized by hepatic steatosis without any alcohol abuse. As the prevalence of NAFLD is rapidly increasing worldwide, important research activity is being dedicated to deciphering the underlying molecular mechanisms in order to define new therapeutic targets. To investigate these pathways and validate preclinical study, reliable, simple and reproducible tools are needed.

GNS561 acts as a potent anti-fibrotic and pro-fibrolytic agent in liver fibrosis through TGF-β1 inhibition.

Background: Hepatic fibrosis is the result of chronic liver injury that can progress to cirrhosis and lead to liver failure. Nevertheless, there are no anti-fibrotic drugs licensed for human use. Here, we investigated the anti-fibrotic activity of GNS561, a new lysosomotropic molecule with high liver tropism.