Renal cell carcinoma (RCC) is the most common type of
kidney cancer, and it appears to be highly susceptible to ferroptosis.
Disulfiram, an
alcoholism drug, has been shown to have anticancer properties in various studies, including those on RCC. However, the mechanism of the anticancer effect of
disulfiram/copper on RCC remains unclear. In this study, we investigated the impact of
disulfiram/copper on RCC treatment using both RCC cells and mouse subcutaneous
tumor models. Our findings demonstrate that
disulfiram/copper treatment reduced the viability of RCC cells, inhibited their invasion and migration, and disrupted mitochondrial homeostasis, ultimately leading to oxidative stress and ferroptosis. Mechanistically,
disulfiram/copper treatment prolonged the half-life of NRF2 and reduced its degradation, but had no effect on transcription, indicating that the
disulfiram/copper-induced increase in NRF2 was not related to transcription. Furthermore, we observed that
disulfiram/copper treatment reduced the expression of NPL4, a
ubiquitin protein-
proteasome system involved in NRF2 degradation, while overexpression of NPL4 reversed NRF2 levels and enhanced
disulfiram/copper-induced oxidative stress and ferroptosis. These results suggest that overcoming the compensatory increase in NRF2 induced by NPL4 inhibition enhances
disulfiram/copper-induced oxidative stress and ferroptosis in RCC. In addition, our in vivo experiments revealed that
disulfiram/copper synergized with
sorafenib to inhibit the growth of RCC cells and induce ferroptosis. In conclusion, our study sheds light on a possible mechanism for
disulfiram/copper treatment in RCC and provides a potential synergistic strategy to overcome
sorafenib resistance.