Investigating Mitochondrial Viscosity in Ferroptosis‐Mediated Drug‐Induced Liver Injury using a Double‐Targeted Strategy

Abstract Investigating mitochondrial viscosity in ferroptosis‐mediated drug‐induced liver injury (DILI) is helpful for the reliable diagnosis and therapy of liver injury. Nevertheless, mitochondrial function and membrane potential may be impaired in the occurrence and development of DILI, so accurately monitoring viscosity changes remains a difficult task. Considering the presence of high expression of mitochondrial uncoupling protein 2 (UCP2) in liver injury, a new near‐infrared fluorescent probe (named FTZ‐2) is presented to investigate the tanglesome relationships between mitochondrial viscosity and ferroptosis‐mediated DILI by introducing a mitochondrial double‐targeted strategy that combined electrostatic reaction and probe–protein docking. The newly synthetized FTZ‐2 is highly selective to environmental viscosity in the presence of reactive species. Owing to its favorable cytotoxicity and mitochondrial localization characteristics, FTZ‐2 is used to monitor viscosity variations in ferroptosis cells and ferroptosis‐mediated DILI mice. The reduction of fluorescence signals indicated that ferrostatin‐1, glutathione, and N‐acetyl‐L‐cysteine can alleviate liver injury. Notably, the high expression of UCP2 is also discovered in the liver of ferroptosis mice and ferroptosis‐mediated DILI mice. Taken together, this work demonstrated a double‐targeted strategy for the early diagnosis and evaluation of liver injury through mitochondrial viscosity variations and contributed to the improvement of the therapeutic effect against liver injury.