Mifepristone protects acetaminophen induced liver injury through NRF2/GSH/GST mediated ferroptosis suppression

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Ferroptosis is an iron-dependent cell death mechanism relevant to diseases such as drug-induced liver injury (DILI).
• Existing research identifies several pathways that antagonize ferroptosis, including xCT/GSH/GPX4 and FSP1/CoQ10.
• Discovering novel anti-ferroptosis pathways is crucial for understanding ferroptosis and developing new therapeutic drugs.

Purpose of the Study:

• To identify novel ferroptosis inhibitors and elucidate their mechanisms of action.
• To investigate the potential of mifepristone (RU486) as a ferroptosis inhibitor.
• To explore the therapeutic efficacy of RU486 in a mouse model of drug-induced liver injury.

Main Methods:

• In vitro cell-based assays to assess ferroptosis inhibition by RU486.
• Mechanistic studies involving glutathione (GSH) synthesis, detoxification enzymes (GSTs), and transporter proteins (RLIP76, MRP1).
• In vivo studies using a mouse model of acetaminophen (APAP)-induced acute liver injury.

Main Results:

• Mifepristone (RU486) was identified as a novel ferroptosis inhibitor.
• RU486 functions by inducing GSH synthesis and activating the NRF2 pathway, leading to enhanced detoxification of harmful byproducts like 4-HNE.
• This RU486-mediated anti-ferroptosis pathway, involving GSH/GST/RLIP76&MRP1, operates independently of previously known ferroptosis defense systems.
• RU486 demonstrated significant hepatoprotective effects in an APAP-induced liver injury mouse model, reducing liver damage markers and oxidative stress.

Conclusions:

• RU486 represents a novel ferroptosis inhibitor that acts through an independent NRF2/GSH/GST/RLIP76&MRP1 mediated detoxification pathway.
• This pathway offers a new target for therapeutic intervention in ferroptosis-related diseases.
• RU486 shows promise as a protective agent against drug-induced liver injury.