In vivo tracking cystine/glutamate antiporter-mediated cysteine/cystine pool under ferroptosis

Abstract

Cysteine/cystine redox couple plays a vital role in maintaining the cellular redox state of living bio-systems. However, the dynamic changes of the intracellular cysteine/cystine pool mediated by cysteine/glutamate transporter (System XC−) in various cellular processes have remained incompletely understood. Here we established a series of strategies around fluorescent probe CP2 for effectively monitoring the intracellular cysteine level in living cells and in vivo zebrafish model, therefore for tracking dynamic changes of system XC−-mediated cysteine/cystine pool under ferroptosis. Living cell imaging and in vivo visualization both revealed that intracellular cysteine levels could be significantly reduced upon blocking system XC− activity and inducing ferroptotic cell death. This kind of blocking was potent against cisplatin-resistant A549R cancer cells, which might bring new potential for treating drug-resistant carcinoma through regulating system XC− and processes of ferroptosis. With further improvements in monitoring tools, understanding of system XC−-mediated cystine/cysteine pool and ferroptosis could certainly offer crucial information in more physiological or pathological processes.