Non-classical ferroptosis inhibition by a small molecule targeting PHB2

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Ferroptosis is a regulated cell death pathway driven by iron-dependent lipid peroxidation.
• Inhibiting ferroptosis is a potential therapeutic strategy for various diseases.
• Existing ferroptosis inhibitors are typically antioxidants or iron-chelators.

Purpose of the Study:

• To identify and characterize a novel ferroptosis inhibitor with a non-classical mechanism of action.
• To elucidate the molecular target and mechanism of the new inhibitor, YL-939.
• To evaluate the therapeutic efficacy of YL-939 in a preclinical model of ferroptosis-related liver injury.

Main Methods:

• Chemical proteomics was employed to identify the biological target of YL-939.
• In vitro assays were used to confirm the interaction between YL-939 and its target.
• Expression levels of iron storage proteins were analyzed.
• A mouse model of acute liver injury was utilized to assess therapeutic effects.

Main Results:

• YL-939 was identified as a novel ferroptosis inhibitor that is neither an antioxidant nor an iron-chelator.
• Chemical proteomics identified prohibitin 2 (PHB2) as the direct target of YL-939.
• YL-939 promotes ferritin expression via PHB2, reducing intracellular iron and ferroptosis susceptibility.
• YL-939 significantly ameliorated liver damage in an acute liver injury model.

Conclusions:

• A non-classical ferroptosis inhibitor, YL-939, targeting PHB2, was discovered.
• A novel regulatory mechanism for ferroptosis involving the PHB2/ferritin/iron axis was revealed.
• YL-939 presents a promising therapeutic candidate for ferroptosis-associated diseases.