Revealing a close link between ferroptosis and drug-induced liver injury with dual-site NIR ratiometric fluorescent probe for mitochondrial peroxynitrite

Drug-induced liver injury (DILI) is a clinically prevalent condition, one of whose pathogenic mechanisms involves overdose or dependent use of drugs such as acetaminophen (APAP). Although ferroptosis-driven by iron metabolism dysregulation and lipid peroxidation accumulation-has been extensively investigated, the theroretical basis for diagnosing DILI remains insufficient. To explore the correlation between DILI and ferroptosis, we developed a dual-reactive-site mitochondria-targeted near-infrared (NIR) ratiometric fluorescent probe (Mito-Rh-B2) for detecting ONOO^–. Mito-Rh-B2 not only differentiated between various drug-induced DILI types but also successfully revealed a dose-dependent increase in ONOO^– level in an APAP-induced DILI model. Furthermore, cell experiments demonstrated a strong association between ONOO^–/GSH level and both DILI and ferroptosis. This study provides new insights for future clinical applications related to DILI and ferroptosis.