英国医学科学MRC实验室（LMS）Jesús Gil团队近期取得重要工作进展，他们研究发现，COPI囊泡的形成和N-肉豆蔻酰化是选择性杀伤衰老细胞的靶点。相关研究成果2023年11月27日在线发表于《自然—细胞生物学》杂志上。

据介绍，选择性杀死衰老细胞的药物（senolytics）可改善癌症、纤维化和年龄相关疾病的预后。尽管它们具有潜力，但人们对影响衰老细胞存活的分子途径的了解是有限的。

为了发现senolytic靶标，研究人员进行了RNAi筛选，并确定了涂层复合体I（COPI）囊泡的形成是衰老细胞的一个缺陷。COPI的遗传或药理学抑制导致高尔基体扩散、功能失调的自噬和衰老细胞的未折叠蛋白反应依赖性凋亡，并且敲低COPI亚基改善了小鼠模型中癌症和纤维化的结果。靶向COPI的药物具有较差的药理学性质，但研究人员发现N-肉豆蔻酰转移酶抑制剂（NMTi）对COPI的表型有抑制作用，并且是有效的抗衰老剂。在癌症和非酒精性脂肪性肝炎模型中，NMTi能选择性消除衰老细胞并改善预后。

总之，这一研究结果表明，衰老细胞依赖于过度活跃的分泌装置，抑制运输会杀死衰老细胞，并有可能治疗各种衰老相关疾病。

附：英文原文

Title: COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cells

Author: McHugh, Domhnall, Sun, Bin, Gutierrez-Muoz, Carmen, Hernndez-Gonzlez, Fernanda, Mellone, Massimiliano, Guiho, Romain, Duran, Imanol, Pombo, Joaquim, Pietrocola, Federico, Birch, Jodie, Kallemeijn, Wouter W., Khadayate, Sanjay, Dharmalingam, Gopuraja, Vernia, Santiago, Tate, Edward W., Martnez-Barbera, Juan Pedro, Withers, Dominic J., Thomas, Gareth J., Serrano, Manuel, Gil, Jess

Issue&Volume: 2023-11-27

Abstract: Drugs that selectively kill senescent cells (senolytics) improve the outcomes of cancer, fibrosis and age-related diseases. Despite their potential, our knowledge of the molecular pathways that affect the survival of senescent cells is limited. To discover senolytic targets, we performed RNAi screens and identified coatomer complex I (COPI) vesicle formation as a liability of senescent cells. Genetic or pharmacological inhibition of COPI results in Golgi dispersal, dysfunctional autophagy, and unfolded protein response-dependent apoptosis of senescent cells, and knockdown of COPI subunits improves the outcomes of cancer and fibrosis in mouse models. Drugs targeting COPI have poor pharmacological properties, but we find that N-myristoyltransferase inhibitors (NMTi) phenocopy COPI inhibition and are potent senolytics. NMTi selectively eliminated senescent cells and improved outcomes in models of cancer and non-alcoholic steatohepatitis. Our results suggest that senescent cells rely on a hyperactive secretory apparatus and that inhibiting trafficking kills senescent cells with the potential to treat various senescence-associated diseases.

DOI: 10.1038/s41556-023-01287-6

Source: https://www.nature.com/articles/s41556-023-01287-6