Visualization of Ferroptosis‐Induced Lipid Peroxidation Using Plasma Membrane‐Specific Fluorescent Probe LipoxPM

Abstract Reactive oxygen species (ROS) play essential roles in cellular processes, but aberrant generation of ROS can damage lipids, proteins, and DNA leading to pathological events such as aging and neurodegenerative diseases. Polyunsaturated fatty acids (PUFAs) are especially susceptible to such oxidative stress. This ROS‐induced lipid peroxidation is a key process of ferroptosis, an iron‐dependent, non‐apoptotic form of cell death. Although lipid peroxidation is an essential event in ferroptosis, current study tools for detecting the oxidation process lack specificity toward a particular membrane type such as plasma membrane. In this study, we present LipoxPM, a novel fluorescent probe that targets lipid peroxidation specifically in plasma membrane over other cellular membranes. LipoxPM features a BODIPY‐based fluorophore and an anionic sulfonate group, enhancing selective accumulation in the plasma membrane. LipoxPM was able to detect ferroptosis‐related lipid peroxidation in live cells, visualizing the spatial distribution of lipid peroxidation in the cell death processes. This probe would enable study of unknown mechanisms of ferroptosis and could potentially facilitate development of therapeutic strategies targeting oxidative stress‐related diseases.