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.

尽管诱导铁死亡（一种铁依赖性非凋亡细胞死亡形式）已成为一种抗癌策略，但铁死亡的代谢基础仍不清楚。在这里，我们发现葡萄糖决定了人胰腺导管癌细胞对药理学抑制系统 xc ^-诱导的铁死亡的敏感性。从机制上讲，SLC2A1介导的葡萄糖摄取促进糖酵解，从而促进丙酮酸氧化，为三环酸循环提供燃料，并刺激脂肪酸合成，最终促进脂质过氧化依赖性铁死亡。通过筛选针对代谢酶的小干扰 RNA (siRNA) 文库，将丙酮酸脱氢酶激酶 4 (PDK4) 鉴定为负责铁死亡抗性的首要基因。 PDK4 通过阻断丙酮酸脱氢酶依赖性丙酮酸氧化来抑制铁死亡。抑制PDK4可增强系统^xc-抑制剂在体外和合适的临床前小鼠模型（例如高脂肪饮食糖尿病模型）中的抗癌活性。这些发现表明代谢重编程是克服铁死亡抗性的潜在目标。