Recoding the Cancer Epigenome by Intervening in Metabolism and Iron Homeostasis with Mitochondria-Targeted Rhenium(I) Complexes

The development and malignancy of cancer cells are closely related to the changes of the epigenome. In this work, a mitochondria-targeted rhenium(I) complex (DFX-Re3), integrating the clinical iron chelating agent deferasirox (DFX), has been designed. By relocating iron to the mitochondria and changing the key metabolic species related to epigenetic modifications,DFX-Re3can elevate the methylation levels of histone, DNA, and RNA. As a consequence,DFX-Re3affects the events related to apoptosis, RNA polymerases, and T-cell receptor signaling pathways. Finally, it is shown thatDFX-Re3induces immunogenic apoptotic cell death and exhibits potent antitumor activity in vivo. This study provides a new approach for the design of novel epigenetic drugs that can recode the cancer epigenome by intervening in mitochondrial metabolism and iron homeostasis.