A Carbonic Anhydrase IX/SLC1A5 axis regulates glutamine metabolism dependent ferroptosis in hypoxic tumor cells.

The ability of tumor cells to alter their metabolism to support survival and growth presents a challenge to effectively treat cancers. Carbonic anhydrase IX (CAIX) is a hypoxia-induced, metabolic enzyme that plays a crucial role in pH regulation in tumor cells. Recently, through a synthetic lethal screen, we identified CAIX to play an important role in redox homeostasis. In this study, we show that CAIX interacts with the glutamine transporter, solute carrier family 1 member 5 (SLC1A5), and coordinately functions to maintain redox homeostasis through the glutathione/glutathione peroxidase 4 (GSH/GPX4) axis. Inhibition of CAIX increases glutamine uptake by SLC1A5 and concomitantly increases GSH levels. The combined inhibition of CAIX activity and glutamine metabolism or the GSH/GPX4 axis results in an increase in lipid peroxidation and induces ferroptosis, both in vitro and in vivo. Thus, this study demonstrates co-targeting of CAIX and glutamine metabolism as a potential strategy to induce ferroptosis in tumor cells.