Turning Off the Powerhouse: Mitochondria-Targeted DPPZ-Ru(II)/Ir(III)/Re(I) Complexes Trigger Dual Mitophagy and Apoptosis To Halt Triple-Negative Breast Cancer

A systematic evaluation of dppz-based Ru(II), Ir(III), and Re(I) complexes has identified [UDRu] as a potent therapeutic candidate against triple-negative breast cancer stem cells (TNBCSCs). [UDRu] exhibits optimal hydrophilic-lipophilic balance, enabling effective solubility, cellular uptake, and mitochondrial targeting. It induces oxidative stress by depleting GSH and NAD(P)H, promotes ROS generation, disrupts mitochondrial membrane potential, causes DNA damage, and arrests the cell cycle at G2/M. Furthermore, [UDRu] inhibits 3D mammosphere formation and triggers apoptosis through BAX/Bcl-2 regulation and caspase-9 activation. Notably, it also triggers mitophagy through PINK1/Parkin upregulation, offering dual mitochondrial-targeted cytotoxicity. These findings position [UDRu] as a next-generation Ru(II) complex with multitargeted action, holding significant promise for overcoming resistance in TNBC therapy.