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

Xinxin Song, Jiao Liu, Feimei Kuang, Xin Chen, Herbert J. Zeh, Rui Kang, Guido Kroemer, Yangchun Xie, Daolin Tang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number108767
JournalCell Reports
Volume34
Issue number8
DOIs
StatePublished - Feb 23 2021

Keywords

  • PDK4
  • cancer
  • fatty acid
  • ferroptosis
  • glucose
  • glycolysis
  • metabolism
  • pyruvate oxidation
  • resistance
  • therapy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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