Heterogeneity of senescent cells underlies resistance to ABT263 and ARV825

ABT263 and ARV825 emerged as promising senolytic candidates based on our criteria. Nevertheless, 20–30% of senescent cells persisted after treatment with these compounds. To investigate why a subset of cells remained refractory, we examined scRNA-seq to profile the surviving population. Notably, several genes encoding V-ATPase subunits—such as ATP6V0E1, which are essential for lysosomal degradation of damaged organella—were consistently enriched in both ABT263- and ARV825-resistant senescent cells. These findings indicate that cells exhibiting elevated V-ATPase activity may evade senolytic action by more efficiently clearing damaged organelles, including mitochondria. Overall design: RNA-seq profiling of early-passage pre-senescent TIG-3 cells and doxorubicin-induced senescent TIG-3 cells with ABT263, ARV825, or vehicle (DMSO) for 7days.