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Mitochondria-Targeted Re (I) Complex Triggers Cuproptosis and Pyroptosis by Regulating Copper/Zinc Homeostasis in
Jiemin Zhang1, Junjian Lu1, Zilong Xu1
1MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, China.
None:
Copper and zinc homeostasis is tightly regulated in mammalian cells, and their dysregulation is implicated in various pathological conditions including cancer. Herein, we have designed rhenium (I) complexes with Cu2+ and Zn2+ chelating properties, exhibiting significant antiproliferative activities against various tumor cell lines. Mechanistic studies have found that mitochondria-targeted complex Re2 induces a substantial increase in the intracellular Cu/Zn levels, especially in the mitochondrial compartment, disrupting the homeostasis of copper and zinc ions in cells and mitochondria, thereby triggering cuproptosis, GSDMD-mediated pyroptosis, and p16/p21-dependent cellular senescence signaling pathway simultaneously. Moreover, co-incubation with copper/zinc ions can further enhance the antitumor activity of Re2 significantly. In the 4T1 murine breast cancer model, Re2 demonstrated potent tumor suppression efficacy with excellent in vivo biocompatibility. This work suggests that intervening in copper and zinc homeostasis is an effective means of regulating multiple programmed cell death, providing new strategies for the rational design of the next-generation metal-based antitumor agents.
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