Modulation of ferroptosis sensitivity by TXNRD1 in pancreatic cancer cells

Abstract The selenoprotein thioredoxin reductase 1 (TXNRD1) plays a central role in ameliorating oxidative stress. Inhibition of TXNRD1 has been explored as a means of killing cancer cells that are thought to develop an enhanced reliance on such antioxidant proteins. In the context of ferroptosis, a non-apoptotic form of oxidative cell death, TXNRD1 has been proposed to cooperate with the phospholipid hydroperoxidase enzyme glutathione peroxidase 4 (GPX4) to protect cells from the lethal accumulation of lipid peroxides. Here, we report our unexpected finding that in pancreatic cancer cells, CRISPR–Cas9-mediated loss of TXNRD1 confers protection from ferroptosis induced by small-molecule inhibition of GPX4. Insights stemming from mechanistic interrogation of this phenomenon suggest that loss of TXNRD1 results in increased levels of GPX4 protein, potentially by influencing availability of selenocysteine, a scarce amino acid required by both proteins for proper synthesis and function. Increased abundance of GPX4 protein, in turn, protects cells from the effects of small-molecule GPX4 inhibition. These findings implicate selenoprotein regulation in governing ferroptosis sensitivity. Furthermore, by delineating a relationship between GPX4 and TXNRD1 contrary to that observed in numerous other settings, our discoveries underscore the context-specific nature of ferroptosis circuitry and its modulators.