ACC Inhibition by Lanatoside C: A Repurposed MASH Therapy

Area of Science:

• Pharmacology
• Hepatology
• Drug Discovery

Background:

• Metabolic Dysfunction-Associated Steatohepatitis (MASH) presents a significant unmet medical need with limited treatment options.
• Acetyl-CoA carboxylase (ACC) inhibition is a potential therapeutic strategy for MASH.
• Development of effective ACC inhibitors for MASH is ongoing.

Purpose of the Study:

• To identify potential ACC inhibitors for MASH through drug repurposing.
• To evaluate the efficacy of candidate compounds in a MASH cell model.
• To investigate the mechanism of action of promising compounds.

Main Methods:

• Structure-based virtual screening of a small-molecule library.
• In vitro validation using a free fatty acid-induced MASH cell model.
• Measurement of triglyceride and AST levels, gene expression analysis (qRT-PCR), and molecular dynamics simulations.

Main Results:

• Lanatoside C was identified as a potent ACC inhibitor.
• Lanatoside C significantly reduced intracellular triglyceride and AST levels in MASH cells.
• Lanatoside C modulated lipid metabolism by downregulating lipogenesis and upregulating fatty acid oxidation genes.

Conclusions:

• Lanatoside C demonstrates dual regulatory effects on lipid metabolism, suppressing synthesis and enhancing oxidation.
• As an FDA-approved drug, Lanatoside C offers a viable repurposing strategy for MASH.
• Further in vivo studies are warranted to validate Lanatoside C for MASH treatment.