Asparaginase and Autophagy Inhibitors Effectively Remove Senescent Cells by Synergistically Limiting Asparagine Supply.

ABSTRACT: The accumulation of senescent cells (SNCs) contributes to tissue dysfunction and age-related diseases, creating an urgent need for effective senolytic strategies. We identified a metabolic vulnerability in SNCs characterized by marked downregulation of asparagine synthetase (ASNS), rendering them uniquely dependent on exogenous asparagine (Asn). This vulnerability was exploited through combined treatment with L-asparaginase (ASNase) and autophagy inhibitors, which synergistically deplete Asn via complementary mechanisms: ASNase degrades extracellular Asn pools, while autophagy inhibition blocks intracellular protein recycling as an alternative Asn source. This dual approach induced selective synthetic lethality across multiple SNC types in vitro. In aged mice, the combination therapy signi

SUBMITTER: Huang Z 

PROVIDER: S-EPMC12507409 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature