PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis

Although induction of ferroptosis, an iron-dependent form of non-apoptotic cell death, has emerged as an anticancer strategy, the metabolic basis of ferroptotic death remains poorly elucidated. Here, we show that glucose determines the sensitivity of human pancreatic ductal carcinoma cells to ferroptosis induced by pharmacologically inhibiting system xc−. Mechanistically, SLC2A1-mediated glucose uptake promotes glycolysis and, thus, facilitates pyruvate oxidation, fuels the tricyclic acid cycle, and stimulates fatty acid synthesis, which finally facilitates lipid peroxidation-dependent ferroptotic death. Screening of a small interfering RNA (siRNA) library targeting metabolic enzymes leads to identification of pyruvate dehydrogenase kinase 4 (PDK4) as the top gene responsible for ferroptosis resistance. PDK4 inhibits ferroptosis by blocking pyruvate dehydrogenase-dependent pyruvate oxidation. Inhibiting PDK4 enhances the anticancer activity of system xc− inhibitors in vitro and in suitable preclinical mouse models (e.g., a high-fat diet diabetes model). These findings reveal metabolic reprogramming as a potential target for overcoming ferroptosis resistance. [Display omitted] •SLC2A1-dependent glucose uptake facilitates ferroptosis•Pyruvate oxidation-dependent fatty acid synthesis facilitates ferroptosis•PDK4 is a key metabolic regulator of ferroptosis resistance•High-fat diet promotes ferroptotic cell death in vivo Song et al. demonstrate that PDK4 plays a role in preventing ferroptosis by inhibiting pyruvate oxidation and subsequent fatty acid synthesis and lipid peroxidation in pancreatic cancer cells. These findings indicate that targeting glucose metabolic pathways has the potential to modulate ferroptosis sensitivity in cancer therapy.