Ginsenoside Rg5 Ameliorates Ferroptosis in Ethanol-Induced Acute Liver Injury by Activating FTO-YTHDF2-Nrf2 Signal

Area of Science:

• Hepatology
• Molecular Biology
• Pharmacology

Background:

• Acute liver injury (ALI) poses a significant health challenge.
• Ginseng, particularly ginsenoside Rg5 (Rg5), is known for its traditional medicinal uses and potential liver-protective effects.
• The Nrf2 pathway is crucial in cellular defense against oxidative stress.

Purpose of the Study:

• To elucidate the mechanism by which Rg5 alleviates ethanol-induced ALI.
• To investigate the role of FTO-mediated m6A demethylation and ferroptosis in Rg5's hepatoprotective action.
• To explore the interplay between FTO, YTHDF2, and Nrf2 in regulating ferroptosis during ALI.

Main Methods:

• Establishment of in vitro (HepG2 cells) and in vivo (C57BL/6J mice) ALI models using ethanol.
• Assessment of reactive oxygen species (ROS), mitochondrial membrane potential, and intracellular iron levels.
• Biochemical analysis of oxidative stress markers, Western blotting for key proteins (FTO, YTHDF2, Nrf2, ACSL4), and HE staining for liver histology.

Main Results:

• Rg5 treatment reduced ferroptosis markers, decreased intracellular iron, and restored mitochondrial function in ethanol-exposed cells and mice.
• FTO knockdown exacerbated ferroptosis, while Rg5 alleviated it by modulating FTO/YTHDF2/Nrf2 signaling.
• Rg5 treatment improved liver function, reduced liver injury, and normalized key protein expressions in vivo.

Conclusions:

• Rg5 alleviates ethanol-induced ALI by inhibiting ferroptosis via the FTO/YTHDF2/Nrf2 axis.
• This study highlights FTO-mediated m6A demethylation as a critical regulator of ferroptosis in ALI.
• The findings provide new mechanistic insights into the hepatoprotective effects of ginsenosides.