Inhibition of PINK1/Parkin-mediated Mitophagy Enhances the Susceptibility of Breast Cancer to Cuproptosis

Cuproptosis is a novel form of programmed cell death characterized by the accumulation of copper ions in the mitochondria, the formation of DLAT oligomers, and the depletion of Fe-S cluster proteins. However, the alterations in mitochondrial morphology and function during cuproptosis and the potential role of mitophagy in cuproptosis remain insufficiently elucidated. In this study, we induced cuproptosis of breast cancer cells using Elesclomol (ES) and assessed changes in mitochondrial reactive oxygen species, mitochondrial membrane potential, and oxygen consumption rate. Stable cell lines with overexpression or knockdown of PINK1/Parkin genes were constructed to elucidate the impact of mitophagy on cuproptosis. Subcutaneous mouse xenograft models were employed to identify drugs that may synergize with ES and enhance antitumor effects. Our results demonstrated that ES induced cuproptosis of breast cancer cells, which was associated with the activation of PINK1/Parkin-mediated mitophagy. Both gene knockdown and pharmacological inhibition of mitophagy enhanced the sensitivity of breast cancer cells to cuproptosis in vitro and in vivo. The combination of dichloroacetate (DCA) and ES exhibited a synergistic antitumor effect without significant tissue damage on the brain, heart, liver, and kidneys in subcutaneous mouse xenograft models. Collectively, our findings reveal that inhibiting PINK1/Parkin-mediated mitophagy enhances the sensitivity of breast cancer to cuproptosis, offering a novel combined treatment strategy for breast cancer.