Multifunctional fluorescent probe for dual monitoring of polarity and HOCl to visualize ferroptosis‑mediated drug‑induced liver injury.

Ferroptosis is a recently characterized, iron-dependent modality of regulated cell death that precipitates organ injury by derailing cellular redox homeostasis and can serve as an indicator of hepatic injury severity. Yet studies linking ferroptosis to liver pathology face two major constraints: (1) fluorescent probes that use iron ions as the analyte suffer interference from specific reaction chemistries, resulting in low sensitivity and poor physiological stability; and (2) the therapeutic promise of modulating ferroptosis in liver injury remains underexplored. To overcome these barriers, this study introduces two non–iron-based biomarkers—lipid droplet polarity and hypochlorous acid-as alternative analytical targets, thereby avoiding the limitations imposed by iron-specific reactions. Accordingly, we engineered NIR-MZY, a dual-responsive probe capable of simultaneously monitoring lipid droplet polarity and hypochlorous acid, thereby assessing the potential of ferroptosis-targeted strategies for the treatment of liver injury. As expected, we tracked dynamic changes in lipid droplet polarity and hypochlorous acid (HOCl) during drug-induced liver injury and visualized their modulation in cellular and zebrafish models under ferroptosis induction and inhibition. These results indicate that manipulating ferroptosis attenuates hepatic damage and substantiate its viability as a therapeutic target. Thus, NIR-MZY emerges as a convenient, sensitive imaging modality that enables precise diagnosis and intervention in ferroptosis-driven liver injury.