Figure 1.

Hypoxia-induced CAIX activity and iron–sulfur clustering are co-vulnerabilities that can be targeted in combination to induce ferroptosis-mediated death of cancer cells. When CAIX is active (CAIX ON) in the presence of NFS1, intracellular pH and reactive oxygen species (ROS) are effectively regulated, resulting in low levels of lipid peroxidation and inhibition of ferroptosis. Combinatorial inhibition of CAIX activity (CAIX OFF) and NFS1 expression results in intracellular acidosis and deregulation of iron-sulfur clustering which leads to increased ROS, induction of lipid peroxidation and promotion of ferroptosis. Treatment strategies designed to inhibit CAIX and induce ferroptosis have the potential to overcome therapeutic resistance in hypoxic tumors. GSH, glutathione; Glu, glutamate.