An ultrasensitive GSH-specific fluorescent probe unveils celastrol-induced ccRCC ferroptosis

Glutathione (GSH) is closely related to the occurrence and development of tumors. The intracellular GSH levels are abnormally altered when tumor cells undergo programmed cell death. Therefore, real-time monitoring of the dynamic changes of intracellular GSH levels can better enable the early diagnosis of diseases and evaluate the effects of cell death-inducing drugs. In this study, a stable and highly selective fluorescent probe AR has been designed and synthesized for the fluorescence imaging and rapid detection of GSH in vitro and in vivo, as well as patient-derived tumor tissue. More importantly, the AR probe can be used to track changes in GSH levels and fluorescence imaging during the treatment of clear cell renal cell carcinoma (ccRCC) with celastrol (CeT) via inducing ferroptosis. These findings demonstrate that the developed fluorescent probe AR exhibits high selectivity and sensitivity, as well as good biocompatibility and long-term stability, which can be used to image endogenous GSH in living tumors and cells. Also, a significant decrease in GSH levels was observed by the fluorescent probe AR during the treatment of ccRCC with CeT-induced ferroptosis in vitro and in vivo. Overall, these findings will provide a novel strategy for celastrol targeting ferroptosis in the treatment of ccRCC and the application of fluorescent probes to help reveal the underlying mechanism of CeT in the treatment of ccRCC.