A PROTAC‐Based Cuproptosis Sensitizer in Lung Cancer Therapy

Abstract As an autonomous form of regulated cell death, cuproptosis depends on copper (Cu) and mitochondrial metabolism. However, the principle metabolic pathway known as glycolysis (Warburg effect) and high glutathione (GSH) levels of tumor cells inevitably lead to suboptimal efficacy in cuproptosis. Hence, depleting the endogenous GSH within tumors and shifting from glycolysis to mitochondrial respiration are crucial factors for augmenting cuproptosis. In this study, a proteolysis targeting chimera (PROTAC)‐based cuproptosis sensitizer (CuS‐MD@CS) is innovatively constructed, which not only can induce cuproptosis and reactive oxygen species production via copper ions but also can regulate the expression of p53 protein via PROTACs through the ubiquitin‐proteasome system in tumor cells, thus achieving endogenous GSH depletion and a shift from glycolysis to mitochondrial respiration, making cancer cells more sensitive to cuproptosis. Importantly, in vitro and in vivo experiments have verified that CuS‐MD@CS effectively targets A549 cells and suppresses tumor growth through cuproptosis and apoptosis, exhibiting promising therapeutic responses. The novel PROTAC‐based cuproptosis sensitizer CuS‐MD@CS provides a new strategy for sensitizing cuproptosis and offers new hope for effective lung cancer treatment.