Ratiometric SERS nanoprobe for ferroptosis monitoring in drug-induced liver injury via accurate detection of hydrogen peroxide in endoplasmic reticulum

Drug-induced liver injury (DILI) is a major liver dysfunction commonly caused by excessive or long-term administration of hepatotoxic drugs. The initiation and development of DILI have been closely related to ferroptosis. Revealing the internal relationship between ferroptosis and DILI is beneficial for the early diagnosis and therapy of DILI. Herein, a unique ratiometric surface-enhanced Raman scattering (SERS) nanoprobe was developed to explore the association between DILI and ferroptosis based on the variations of hydrogen peroxide (H₂O₂) in endoplasmic reticulum (ER). The SERS nanoprobe is composed of an ER-targeting peptide and an H₂O₂-responsive Raman reporter (3-mercaptophenylboronic acid), which shows a remarkable ratiometric SERS change (I_1071/998) for H₂O₂ with high selectivity and sensitivity. Using the nanoprobe, the dynamic alterations of H₂O₂ levels in ER within hepatocytes were successfully tracked throughout both the induction and inhibition of ferroptosis. Moreover, the complex interplay between ferroptosis and DILI in both cellular and murine models were elucidated. Complemented by Western blot analysis, the possible therapeutic effect of ferroptosis inhibition on DILI was confirmed by improving the Xc-/GSH/GPX4 antioxidant system. This study presents a novel approach for studying the relationship between ferroptosis and liver injury, thereby advancing DILI diagnosis and treatment.