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, III,
Rui Kang,
Guido Kroemer,
Yangchun Xie,
Daolin Tang
Affiliations
Xinxin Song
Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
Jiao Liu
The Third Affiliated Hospital, Guangzhou Medical University, Guangdong, China
Feimei Kuang
The Third Affiliated Hospital, Guangzhou Medical University, Guangdong, China
Xin Chen
Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
Herbert J. Zeh, III
Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
Rui Kang
Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
Guido Kroemer
Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France; Institut National de la Santé et de la Recherche Médicale, U1138, Paris, France; Université Pierre et Marie Curie, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France; Department of Women’s and Children’s Health, Karolinska University Hospital, 17176 Stockholm, Sweden
Yangchun Xie
Department of Oncology, The Second Xiangya Hospital, Central South University, Hunan, China; Corresponding author
Daolin Tang
Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA; Corresponding author
Summary: 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.
