2. Academic Validation
  3. Metabolic rewiring driven by phosphoglycolate phosphatase deletion inhibits ferroptosis

Metabolic rewiring driven by phosphoglycolate phosphatase deletion inhibits ferroptosis

  • Sci Adv. 2026 May 29;12(22):eaeb2368. doi: 10.1126/sciadv.aeb2368.
Marian Brenner 1,  Sina Höhlein 1,  Paul Wirth 1,  Leon Neidt 1,  Melina Lappe 1,  Elisa Hopke 1,  Eirini Sfakianaki 1,  Martina Fischer 1,  Kerstin Hadamek 1,  Angelika Keller 1,  Sebastian Bothe 2 3,  José Pedro Friedmann Angeli 2,  Anna M Schmoker 4,  Arminja N Kettenbach 4 5,  Agnes Fekete 6,  Werner Schmitz 7,  Ingrid Tessmer 2,  Elisabeth Jeanclos 1,  Antje Gohla 1
Affiliations

Affiliations

  • 1 Institute for Pharmacology and Toxicology, University of Würzburg, Germany.
  • 2 Rudolf-Virchow-Zentrum-Center for Integrative and Translational Bioimaging, University of Würzburg, Germany.
  • 3 Institute of Pharmacy and Food Chemistry, University of Würzburg, Germany.
  • 4 Dartmouth Cancer Center, Lebanon, NH, USA.
  • 5 Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
  • 6 Pharmaceutical Biology, Julius von Sachs Institute and Biocenter, University of Würzburg, Germany.
  • 7 Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, Germany.
PMID: 42213853 DOI: 10.1126/sciadv.aeb2368
Abstract

Modulating Ferroptosis, a form of cell death driven by uncontrolled lipid peroxidation, is of interest in numerous diseases. Here, we found that the deletion of phosphoglycolate Phosphatase (PGP), an essential enzyme that safeguards high glycolytic flux, suppresses Ferroptosis. Using metabolomic and isotopic labeling experiments together with lipid and proteomic profiling, we find that PGP loss drives a rewiring of the pentose phosphate pathway and of cellular energy and lipid metabolism that triggers a multifactorial antioxidant response. Paradoxically, our attempts to block PGP pharmacologically led to the realization that the recently described PGP inhibitor compound 1 (CP1) exerts a strong ferroptosis-sensitizing effect. Using genetic, biochemical, and biophysical approaches, we characterize CP1 as a direct, species-independent, dual inhibitor of PGP and Ferroptosis suppressor protein 1 (FSP1), and further find that CP1 triggers FSP1 self-assembly. In sum, we identify PGP as a target protein for Ferroptosis control and introduce a small-molecule FSP1 inhibitor with unique features to the armamentarium of pharmacological Ferroptosis modulators.

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