Investigating the Therapeutic Effects of Ferroptosis on Myocardial Ischemia‐Reperfusion Injury Using Dual‐Locking Mitochondrial Targeting Strategy

Research of ferroptosis in myocardial ischemia/reperfusion injury (MIRI) using mitochondrial viscosity as a nexus holds great promise for MIRI therapeutics. However, high precision visualizing mitochondrial viscosity remains a formidable task owing to the debilitating electrostatic interaction caused by damaged mitochondrial membrane potential. Herein, we proposed a dual‐locking mitochondrial targeting strategy that incorporates the idea of electrostatic forces and probe‐protein molecular docking. Even in the damaged mitochondria, stable and precise visualization of mitochondrial viscosity in triggered and medicated MIRI was achieved owing to the sustained driving forces (pi‐cation, pi‐alkyl interactions etc.) between the developed probe CBS and mitochondrial membrane protein. Moreover, complemented by the western blot technology, we confirmed that ferrostatin‐1 exerts its therapeutic effect on MIRI by improving the system xc−/GSH/GPX4 antioxidant system, confirming the therapeutic value of ferroptosis in MIRI. This work presents a new strategy for developing robust mitochondrial probes, thereby advancing the treatments for MIRI.