Luo Xianyu, Linghu Maoyuan, Zhou Xinru, Ru Yi, Huang Qian, Liu Didi, Ji Shurong, Ma Yinchu, Luo Yingli, Huang Yi
Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China.
Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China.
Free Radic Biol Med. 2025 Mar 1;229:68-81. doi: 10.1016/j.freeradbiomed.2025.01.029. Epub 2025 Jan 15.
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-CuCl (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.
铜死亡是一种新型的程序性细胞死亡形式，由过量的铜离子诱导产生，并与多种疾病的进展有关，包括肝损伤、心血管疾病和神经退行性疾病。然而，目前在治疗中尚无针对特定铜死亡相关途径的抑制剂。在此，通过筛选激酶抑制剂文库，化合物美瑞替尼（MTB）被鉴定为一种强力的铜死亡抑制剂。结果表明，MTB通过阻止脂酰化蛋白的聚集和铁硫簇蛋白的不稳定，有效阻断依斯氯铵 - 氯化铜（ES - Cu）诱导的铜死亡，从而防止蛋白毒性应激并最终避免细胞死亡。从机制上讲，MTB通过直接与NRF2结合来降低氧化应激水平。此外，它提高了铜稳态的效率，并促进铜离子的胞吐和转运，最终抑制铜死亡。此外，我们的研究表明MTB有能力减轻小鼠中铜死亡驱动的急性肝损伤。这些发现表明MTB是一种特异性的铜死亡抑制剂，为铜死亡相关疾病的治疗方法提供了一个有希望的选择。
