Tumors fueled by a cancer gene named KRAS are often susceptible to ferroptosis, a type of cell death caused by the iron-driven oxidation of membrane lipids. Yet, though more than 95% of pancreatic ductal adenocarcinomas (PDACs) harbor KRAS mutations, they show no such vulnerability. Researchers led by Ludwig Institute CEO and Scientific Director Chi Van Dang and Maimon Hubbi, a postdoc in his laboratory at Johns Hopkins University, reported in an April paper in Molecular Cell that the composition of metabolites in the fluid around PDAC cells and the tumor’s typically severe hypoxia cooperate to induce resistance to ferroptosis. They also identified hypoxia-inducible factor-2 (HIF-2) as a critical mediator of this effect. Maimon, Chi and their colleagues showed that HIF-2 boosts levels of glutathione, a cofactor for the enzyme GPX4, which counters the lethal membrane oxidation driven by ferroptosis. It does so by stepping up expression of the Xc– transporter, which brings the molecule’s precursor (cystine) into the cells, as well as that of enzymes (CBS and CTH) that help convert precursors into glutathione. It also stimulates mitophagy and reduces mitochondrial production of reactive oxygen species, limiting the lipid peroxidation that drives ferroptosis. The findings suggest targeting HIF-2-activated pathways could sensitize pancreatic tumors to ferroptotic therapies.
The HIF-2 transcription factor mediates resistance to ferroptosis in pancreatic cancer
Molecular Cell, 2026 April 2