Highlights d Most cancer cell lines are largely insensitive to GSH depletion d Deubiquitinases (DUBs) protect cancer cells upon inhibition of GSH synthesis d Inhibition of DUBs and GSH synthesis causes ER and proteotoxic stress and cell death d Combined targeting of DUBs and GSH blocks tumor growth

Current systems for modulating the abundance of proteins of interest in living cells are powerful tools for studying protein function but differ in terms of their complexity and ease of use. Moreover, no one system is ideal for all applications, and the best system for a given protein of interest must often be determined empirically. The thalidomide-like molecules (collectively called the IMiDs) bind to the ubiquitously expressed cereblon ubiquitin ligase complex and alter its substrate specificity such that it targets the IKZF1 and IKZF3 lymphocyte transcription factors for destruction. Here, we mapped the minimal IMiD-responsive IKZF3 degron and show that this peptidic degron can be used to target heterologous proteins for destruction with IMiDs in a time- and dose-dependent manner in cultured cells grown ex vivo or in vivo.