Multi-target regulation by artemether in MAFLD through EGFR/HSP90 pathways

Area of Science:

• Hepatology
• Pharmacology
• Molecular Biology

Background:

• Metabolic dysfunction-associated fatty liver disease (MAFLD) prevalence is increasing, with limited treatment options.
• Artemether (Art), an artemisinin derivative, shows promise for MAFLD but its molecular targets are unknown.

Purpose of the Study:

• To investigate the therapeutic effects of Art on MAFLD.
• To identify the direct molecular targets of Art in MAFLD.

Main Methods:

• MAFLD was induced in mice using high-fat diets and treated with Art.
• In vitro studies used fatty acid-induced MAFLD models in hepatocytes treated with Art.
• Protein target identification involved DARTS, CESTA, chemical proteomics, and molecular docking.

Main Results:

• Art reduced hepatic lipid accumulation in vivo and in vitro.
• Heat shock protein 90 (HSP90) and epidermal growth factor receptor (EGFR) were identified as direct targets of Art.
• Art disrupted the HSP90-EGFR complex, decreasing EGFR stability and expression.

Conclusions:

• EGFR is a key molecular target of Art in MAFLD, modulated via HSP90.
• These findings elucidate Art's multi-target mechanism for MAFLD treatment.