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Updated: Sep 14, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Discovery of Potent Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) Inhibitors with Antiferroptotic Properties
Emeline Charnelle1, Alexandre Gobert1, Romain Marteau2
1Univ. Lille, Inserm, CHU Lille, UMR-S-U1172 - LilNCog - Lille Neuroscience & Cognition, Lille F-59000, France.
Abstract:
Ferroptosis, an iron-dependent regulated cell death, is implicated in several diseases, including cancer and neurodegeneration. While most ferroptosis inhibitors act as radical-trapping antioxidants, direct modulation of pro-ferroptotic enzymes remains underexplored. Acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), a key regulator of ferroptosis, has emerged as a promising therapeutic target. Here, we report a fragment-based screening that identified a benzofuran hit (compound 8, IC50 = 33 μM), leading to the discovery of two selective ACSL4 inhibitors: compound 15b (LIBX-A402, IC50 = 0.33 μM) and compound 21 (LIBX-A403, IC50 = 0.049 μM). Compound 21 is the most potent ACSL4 inhibitor reported to date and shows no activity against ACSL3. Molecular modeling and mutagenesis support its binding in the ACSL4 fatty acid pocket. The strong antiferroptotic activity of both compounds in cells, together with confirmed target engagement for 21, underscores the relevance of ACSL4 as a target for ferroptosis modulation.
Insights
Researchers discovered potent inhibitors of ACSL4, a key enzyme in ferroptosis, a cell death process linked to cancer and neurodegeneration. These new compounds offer a novel therapeutic strategy by directly targeting ACSL4.
Area of Science:
- Biochemistry
- Cell Biology
- Medicinal Chemistry
Background:
- Ferroptosis is an iron-dependent regulated cell death implicated in diseases like cancer and neurodegeneration.
- Current ferroptosis inhibitors primarily function as radical-trapping antioxidants, leaving direct enzyme modulation underexplored.
- Acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) is a critical regulator of ferroptosis and a potential therapeutic target.
Purpose of the Study:
- To identify and develop novel, selective inhibitors of ACSL4.
- To explore the potential of targeting ACSL4 for modulating ferroptosis.
Main Methods:
- Fragment-based screening to identify initial hits.
- Lead optimization to discover potent and selective ACSL4 inhibitors.
- Molecular modeling and mutagenesis to elucidate binding mechanisms.
- In vitro assays to assess enzyme inhibition and cellular antiferroptotic activity.
Main Results:
- A benzofuran fragment (compound 8) was identified as an initial hit.
- Two potent and selective ACSL4 inhibitors, compound 15b (LIBX-A402) and compound 21 (LIBX-A403), were discovered.
- Compound 21 exhibits the highest potency (IC50 = 0.049 μM) and selectivity against ACSL3.
- Molecular modeling confirmed compound 21 binds within the ACSL4 fatty acid pocket.
- Both compounds demonstrated significant antiferroptotic activity in cellular assays.
Conclusions:
- ACSL4 is a validated and promising target for therapeutic intervention in ferroptosis.
- The developed inhibitors, particularly compound 21, represent significant advancements in targeting ACSL4.
- Direct modulation of ACSL4 offers a novel strategy for controlling ferroptosis in disease contexts.
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