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Merestinib inhibits cuproptosis by targeting NRF2 to alleviate acute liver injury
Xianyu Luo1, Maoyuan Linghu1, Xinru Zhou1
1Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China.
Abstract:
The emergence of cuproptosis, a novel form of regulated cell death, is induced by an excess of copper ions and has been associated with the progression of multiple diseases, including liver injury, cardiovascular disease, and neurodegenerative disorders. However, there are currently no inhibitors available for targeting specific cuproptosis-related pathways in therapy. Here, the compound merestinib (MTB) has been identified as a strong inhibitor of cuproptosis through screening of a kinase inhibitor library. The results show that MTB effectively blocks elesclomol-CuCl2 (ES-Cu) induced cuproptosis by preventing the aggregation of lipoylated proteins and the destabilization of Fe-S cluster proteins, thereby preventing proteotoxic stress and ultimately cell death. Mechanistically, MTB decreases oxidative stress levels by binding directly to NRF2. Additionally, it boosts the efficiency of the copper homeostasis and facilitates the exocytosis and transportation of copper ions, ultimately inhibiting cuproptosis. Furthermore, our research showed that MTB has the ability to alleviate cuproptosis-driven acute liver injury in mice. These findings suggest that MTB is a specific inhibitor of cuproptosis, presenting a hopeful option for therapeutic approaches in cuproptosis-related diseases.
Insights
Merestinib (MTB) effectively inhibits cuproptosis, a copper-induced cell death linked to diseases. This compound shows promise for treating liver injury and other cuproptosis-related conditions.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Cuproptosis is a novel cell death pathway triggered by excess copper ions.
- This process is implicated in liver injury, cardiovascular disease, and neurodegenerative disorders.
- Targeted therapies for cuproptosis are currently lacking.
Purpose of the Study:
- To identify specific inhibitors of cuproptosis.
- To investigate the therapeutic potential of merestinib (MTB) in blocking cuproptosis.
Main Methods:
- Screening of a kinase inhibitor library to identify cuproptosis inhibitors.
- Assessing MTB's effect on elesclomol-CuCl2 (ES-Cu) induced cuproptosis.
- Investigating MTB's mechanism of action, including its effect on protein aggregation, oxidative stress, and copper homeostasis.
- Evaluating MTB's efficacy in an animal model of acute liver injury.
Main Results:
- Merestinib (MTB) was identified as a potent inhibitor of cuproptosis.
- MTB prevents lipoylated protein aggregation and Fe-S cluster protein destabilization, mitigating proteotoxic stress.
- MTB binds to NRF2, reducing oxidative stress and enhancing copper homeostasis.
- MTB administration alleviated cuproptosis-induced acute liver injury in mice.
Conclusions:
- Merestinib (MTB) is a specific inhibitor of cuproptosis.
- MTB demonstrates therapeutic potential for diseases associated with cuproptosis.
- MTB offers a promising avenue for developing novel treatments for cuproptosis-related pathologies.
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