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

Abstract Research on ferroptosis in myocardial ischemia/reperfusion injury (MIRI) using mitochondrial viscosity as a nexus holds great promise for MIRI therapy. However, high‐precision visualisation of mitochondrial viscosity remains a formidable task owing to the debilitating electrostatic interactions caused by damaged mitochondrial membrane potential. Herein, we propose a dual‐locking mitochondria‐targeting strategy that incorporates electrostatic forces and probe‐protein molecular docking. Even in damaged mitochondria, stable and precise visualisation of mitochondrial viscosity in triggered and medicated MIRI was achieved owing to the sustained driving forces (e.g., pi‐cation, pi‐alkyl interactions, etc.) between the developed probe, CBS , and the mitochondrial membrane protein. Moreover, complemented by a western blot, 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 study presents a novel strategy for developing robust mitochondrial probes, thereby advancing MIRI treatment.