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Discovery of a NCOA4 Degrader for Labile Iron-Dependent Ferroptosis Inhibition
Jian'ai Ji1,2, Yuhui Jin1,3, Sinan Ma1
1Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Abstract:
Ferroptosis, a distinctive form of programmed cell death, has been implicated in numerous pathological conditions, and its inhibition is considered a promising therapeutic strategy. Currently, there is a scarcity of efficient antagonists for directly regulating intracellular ferrous iron. Ferritinophagy, an essential process for supplying intracellular labile iron, relies on nuclear receptor coactivator 4 (NCOA4), a selective autophagy receptor for the ferritin iron storage complex, thus playing a pivotal role in ferritinophagy. In this study, we reported a novel von Hippel-Lindau-based NCOA4 degrader, V3, as a potent ferroptosis inhibitor with an intracellular ferrous iron inhibition mechanism. V3 significantly reduced NCOA4 levels and downregulated intracellular ferrous iron (Fe2+) levels, thereby effectively suppressing ferroptosis induced by multiple pathways within cells and alleviating liver damage. This research presents a chemical knockdown tool targeting NCOA4 for further exploration into intracellular ferrous iron in ferroptosis, offering a promising therapeutic avenue for ferroptosis-related acute liver injury.
Insights
Researchers developed V3, a novel compound targeting NCOA4, to inhibit ferroptosis. This inhibitor reduces intracellular ferrous iron levels, offering a potential treatment for ferroptosis-related liver injury.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Ferroptosis, a programmed cell death pathway, is linked to various diseases, making its inhibition a therapeutic target.
- Regulating intracellular ferrous iron is crucial for controlling ferroptosis, but efficient antagonists are lacking.
- Ferritinophagy, regulated by NCOA4, is a key source of intracellular iron.
Purpose of the Study:
- To develop a novel inhibitor for ferroptosis by targeting NCOA4.
- To investigate the mechanism of intracellular ferrous iron regulation in ferroptosis.
- To evaluate the therapeutic potential of the novel inhibitor in liver injury models.
Main Methods:
- Development of a von Hippel-Lindau-based NCOA4 degrader, designated V3.
- Assessment of V3's effect on NCOA4 levels and intracellular ferrous iron (Fe2+) concentration.
- Evaluation of V3's efficacy in suppressing ferroptosis induced by various stimuli.
- Testing V3's ability to alleviate liver damage in relevant models.
Main Results:
- V3 effectively reduced NCOA4 protein levels.
- V3 significantly decreased intracellular ferrous iron (Fe2+) levels.
- V3 suppressed ferroptosis induced by multiple pathways.
- V3 demonstrated a protective effect against liver damage.
Conclusions:
- V3 acts as a potent ferroptosis inhibitor by reducing NCOA4 and intracellular ferrous iron.
- This study introduces a chemical tool for exploring intracellular iron's role in ferroptosis.
- V3 presents a promising therapeutic strategy for ferroptosis-related acute liver injury.
