Ginsenoside Rg1 alleviates MASH by targeting GLS2 to enhance PINK1/Parkin-mediated mitophagy and improve...

Area of Science:

• Hepatology
• Mitochondrial Biology
• Pharmacology

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is a growing global health concern with limited treatments.
• Improving mitochondrial function and mitophagy are emerging therapeutic strategies for MASH.
• The precise mechanisms and targets of Ginsenoside Rg1 (G-Rg1) in MASH are not fully understood.

Purpose of the Study:

• To investigate if G-Rg1 ameliorates diet-induced MASH by promoting mitophagy.
• To identify the direct molecular target of G-Rg1 in MASH treatment.

Main Methods:

• Histological, biochemical, and calorimetric analyses in mice treated with G-Rg1.
• Transcriptomic profiling and transmission electron microscopy to assess mitophagy and mitochondrial structure.
• Virtual screening, molecular docking, and biochemical assays (dAta, cELISA, binding assays) to identify and confirm G-Rg1's target.

Main Results:

• G-Rg1 treatment improved hepatic steatosis, fibrosis, inflammation, and energy metabolism in MASH mice.
• Enhanced mitophagy and improved mitochondrial ultrastructure were observed post-G-Rg1 treatment.
• Glutaminase 2 (GLS2) was identified as a direct target of G-Rg1, activating the GLS2/PINK1/Parkin pathway, increasing mitophagy, reducing lipid accumulation, and restoring mitochondrial function.

Conclusions:

• G-Rg1 alleviates MASH by targeting GLS2 to activate PINK1/Parkin-mediated mitophagy.
• GLS2-regulated mitophagy represents a promising therapeutic avenue for MASH.
• G-Rg1 demonstrates potential as a therapeutic agent for MASH through its effects on mitochondrial quality control.