选择性消除受损细胞是一种针对老龄相关疾病的不断发展的治疗方法。目前用于鉴定可能促进受损或衰老细胞死亡的基因的全基因组筛选方法通常处于低功效状态，因为细胞死亡的时间尺度较短，而非分裂细胞的扩展艰难。在这里，我们建立了一种称为“Death-seq”的正选择CRISPR筛选方法，用于识别细胞死亡的增强剂和机制。我们的筛选获得了已知的老年细胞溶解剂ABT-263诱导的细胞死亡的协同增强剂。该筛选还在与ABT-263相似但具有较低毒性的相关化合物ABT-199模型中，识别出导致细胞死亡和老年细胞清除的诱导剂，ABT-199本身并不具有老年细胞溶解作用。Death-seq能够系统筛选细胞死亡途径，揭示调节细胞死亡子程序的分子机制，并识别出治疗老化、癌症和纤维化等多种病理状态的药物靶点。版权© 2023 Elsevier Inc. 保留所有权利。

Selectively ablating damaged cells is an evolving therapeutic approach for age-related disease. Current methods for genome-wide screens to identify genes whose deletion might promote the death of damaged or senescent cells are generally underpowered because of the short timescales of cell death as well as the difficulty of scaling non-dividing cells. Here, we establish "Death-seq," a positive-selection CRISPR screen optimized to identify enhancers and mechanisms of cell death. Our screens identified synergistic enhancers of cell death induced by the known senolytic ABT-263. The screen also identified inducers of cell death and senescent cell clearance in models of age-related diseases by a related compound, ABT-199, which alone is not senolytic but exhibits less toxicity than ABT-263. Death-seq enables the systematic screening of cell death pathways to uncover molecular mechanisms of regulated cell death subroutines and identifies drug targets for the treatment of diverse pathological states such as senescence, cancer, and fibrosis.Copyright © 2023 Elsevier Inc. All rights reserved.