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Updated: Sep 16, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Covalent inhibition of ACSL4 alleviates ferroptosis-induced acute liver injury
Maoyuan Linghu1, Xianyu Luo1, Xinru Zhou1
1Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
Abstract:
Ferroptosis, a form of regulated cell death, is characterized by iron-dependent phospholipid peroxidation and is closely linked to various liver diseases. Although covalent inhibitors have gained attention for their high potency and prolonged effects, no specific covalent inhibitor for ferroptosis exists. Here, we identify Rociletinib (ROC) as a potent inhibitor of ferroptosis through virtual screening and mechanistic studies. Our results demonstrate that ROC covalently binds to cysteine 170 of ACSL4, inhibiting its enzymatic activity and thereby suppressing lipid peroxidation and ferroptosis. ROC effectively mitigates ferroptosis-mediated acute liver injury in mouse models. These findings establish ROC as the targeted covalent inhibitor directly targeting ACSL4, offering a promising therapeutic strategy for ferroptosis-related diseases.
Insights
Rociletinib (ROC) is identified as a covalent inhibitor targeting ACSL4, effectively suppressing ferroptosis and lipid peroxidation. This discovery offers a new therapeutic approach for treating ferroptosis-related liver diseases.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Ferroptosis is a regulated cell death pathway driven by iron-dependent lipid peroxidation.
- Ferroptosis is implicated in the pathogenesis of various liver diseases.
- Targeted covalent inhibitors offer high potency and prolonged therapeutic effects.
Purpose of the Study:
- To identify a specific covalent inhibitor for ferroptosis.
- To investigate the mechanism of action of potential ferroptosis inhibitors.
- To evaluate the therapeutic potential of identified inhibitors in liver injury models.
Main Methods:
- Virtual screening was employed to identify potential ferroptosis inhibitors.
- Mechanistic studies were conducted to elucidate the mode of action.
- Inhibition of ACSL4 enzymatic activity and lipid peroxidation was assessed.
- Efficacy was evaluated in mouse models of ferroptosis-mediated acute liver injury.
Main Results:
- Rociletinib (ROC) was identified as a potent inhibitor of ferroptosis.
- ROC covalently binds to cysteine 170 of ACSL4, inhibiting its activity.
- ROC suppresses lipid peroxidation and ferroptosis.
- ROC effectively ameliorates ferroptosis-induced acute liver injury in mice.
Conclusions:
- Rociletinib is the first targeted covalent inhibitor of ACSL4.
- ROC demonstrates therapeutic potential for ferroptosis-related liver diseases.
- Targeting ACSL4 with covalent inhibitors presents a promising strategy for treating ferroptosis.
