Identification of a targeted ACSL4 inhibitor to treat ferroptosis-related diseases

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Ferroptosis, a regulated cell death pathway driven by lipid peroxidation, is implicated in various diseases.
• Specific inhibitors targeting ferroptosis are currently lacking, hindering therapeutic development.

Purpose of the Study:

• To identify and characterize novel, specific inhibitors of ferroptosis.
• To investigate the therapeutic potential of identified inhibitors in disease models.

Main Methods:

• Screening of a kinase inhibitor library to identify ferroptosis inhibitors.
• In vitro studies using human and mouse cells to assess inhibition of lipid peroxidation and ferroptosis.
• Biochemical assays to determine the mechanism of action, including target identification (ACSL4).
• In vivo studies using nanoparticle-based delivery systems in mouse models of organ injury.

Main Results:

• AS-252424 (AS) was identified as a potent inhibitor of ferroptosis and lipid peroxidation in cellular models.
• AS directly binds to ACSL4, inhibiting its enzymatic activity and consequently suppressing ferroptosis.
• AS-loaded nanoparticles effectively ameliorated ferroptosis-mediated kidney ischemia/reperfusion injury and acute liver injury in mice.

Conclusions:

• AS-252424 is a specific inhibitor of ACSL4 with significant antiferroptosis activity.
• Targeting ACSL4 with AS presents a promising therapeutic approach for ferroptosis-related diseases.
• Nanoparticle-mediated delivery of AS demonstrates therapeutic efficacy in preclinical models of organ injury.