Monitoring cysteine changes and assessing ferroptosis in diabetic mice with a lysosome-targeted near-infrared fluorescence probe

Diabetes, characterized by elevated blood sugar levels, often leads to various complications. Cysteine (Cys), a biomarker of oxidative stress, is crucial in the progression of diabetes and its complications. Unfortunately, up until now, fluorescent probes for imaging lysosomal Cys in diabetic mouse models have not been available. Ferroptosis, linked to antioxidant damage in the lysosomal Cys/GPX4 axis, plays a significant role in diabetes. Visualizing lysosomal Cys is vital for assessing ferroptosis and understanding diabetes. We introduce a new near-infrared (NIR) fluorescent probe, NIR-Lys-Cys , designed to detect lysosomal Cys in living cells and diabetic mouse models. This probe shows exceptional selectivity and sensitivity towards Cys, along with superior fluorescence characteristics, enabling detection of Cys in living cells. NIR-Lys-Cys can monitor ferroptosis and its inhibition by measuring lysosomal Cys levels and has been used to detect ferroptosis in glucose-induced diabetic cells. It revealed significantly lower Cys concentrations in the livers of diabetic mice compared to healthy controls. Administering antidiabetic medication increased Cys production in diabetic mice. These findings highlight the potential of NIR-Lys-Cys as a tool for elucidating the role of Cys in lysosome-related diseases, providing critical insights into diagnosis and treatment strategies for diabetes and its complications. • A novel lysosome-targeted NIR fluorescent probe NIR-Lys-Cys is developed. • The probe is capable for imaging of ferroptosis and its inhibition. • Cys-triggered probe applied in diabetic mice models of both the development and treatment. • Achieving characterizing the status of diabetic process via monitoring the lysosome Cys for the first time.