Activation of Synergistic Ferroptosis and Apoptosis by a Cu(II) Complex through Concurrent Amplification of...

The functional crosstalk between endoplasmic reticulum (ER) and mitochondria offers a promising target for cancer therapy, yet achieving precise and synchronous disruption of this interorganelle network remains a major challenge. Here, we report a molecular strategy based on pyridine-hydrazone-derived Cu(II) complexes (Cu1-Cu7), among which Cu2 exhibits potent and selective cytotoxicity. Mechanistically, Cu2 disrupts cellular redox homeostasis by depleting glutathione and generating hydroxyl radicals via a Cu²⁺/Cu⁺ redox cycle. This redox imbalance initiates mitochondrial dysfunction and concurrently triggers ER stress, leading to Ca²⁺ release and subsequent mitochondrial Ca²⁺ overload. These events establish a self-amplifying ROS-Ca²⁺ feedback loop that drives synergistic ferroptosis and apoptosis. Notably, Cu2 demonstrates significant antitumor and antimetastatic efficacy in a cervical cancer model, with minimal systemic toxicity and desirable biocompatibility. This work highlights the innovative use of copper-based complexes to manipulate organelle communication networks precisely, providing a new paradigm for metal-based anticancer agents.