Apoptotic resistance of tumor often leads to poor efficacy from mono-therapy based on apoptosis. Cuproptosis, a new type of non-apoptotic cell death related to mitochondrial dysfunction, can alter metabolism and enhance ferroptosis, providing a promising strategy for effective synergistic cancer treatment. In this work, Cu-based nanoparticles (denoted as HA-ZCu) were successfully developed to improve anti-tumor efficacy by combining cuproptosis with enhanced ferroptosis, which was achieved by cuproptosis-induced glutathione synthesis disorder. In vitro studies revealed that HA-ZCu effectively induced cuproptosis and ferroptosis in HepG2 cells. Moreover, HA-ZCu induced mitochondrial dysfunction and decreased intracellular adenosine triphosphate (ATP), glutamate, and glutathione, demonstrating the effective synergy. In vivo studies further approved the synergistic therapeutic efficacy of HA-ZCu, where the inhibition rate of tumor growth reached 83.2 %. This work represents the first example of enhanced anti-tumor efficacy via cuproptosis and ferroptosis synergy through cuproptosis-induced glutathione synthesis disorder.