A Near-InfraredFluorescent Probe for Imaging NitroxylDynamics in Ferroptosis-Associated Drug-Induced Liver Injury

Abstract As a global health challenge, drug-induced liver injury (DILI) is an acute inflammatory disease closely linked to ferroptosis. Ferroptosis, characterized by iron-dependent lipid peroxidation, has been implicated in diverse pathological conditions, however, its precise molecular mechanism in liver injury remains to be fully elucidated. As a key active nitrogen species, the concentration fluctuation of nitroxyl (HNO) is closely correlated with ferroptosis. Nevertheless, in situ and real-time monitoring of endogenous HNO remains highly challenging owing to its transient lifespan and prominent reactivity. To address this issue, we constructed a near-infrared fluorescent probe specifically activated by HNO to delineate the intrinsic interplay between ferroptosis and DILI, thereby facilitating early diagnosis. This probe features a rapid response rate, extremely specificity, high sensitivity, and outstanding photostability, successfully achieving precise detection and imaging of both exogenous and endogenous HNO in vitro and in vivo. Crucially, real-time monitoring of the dynamic fluctuations of HNO levels with the probe explicitly unveiled a tight correlation of the ferroptosis process with DILI. Notably, inhibiting ferroptosis could significantly alleviate the progression of liver injury. Overall, this work not only provides a powerful molecular tool for the diagnosis of ferroptosis-associated liver diseases, but also offers important theoretical foundations and new strategies for the early clinical intervention of liver injury and related drug screening.