Metabolic rewiring driven by phosphoglycolate phosphatase deletion inhibits ferroptosis
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.
Authors
- Eirini Sfakianaki
- Elisa Hopke
- Antje Gohla (ORCID: https://orcid.org/0000-0002-7442-1487)
- Kerstin Hadamek
- Sebastian Bothe (ORCID: https://orcid.org/0000-0001-6408-6112)
- Anna M. Schmoker (ORCID: https://orcid.org/0000-0003-2830-5650)
- Werner Schmitz (ORCID: https://orcid.org/0000-0003-0485-7303)
- Ingrid Teßmer (ORCID: https://orcid.org/0000-0002-8353-6315)
- José Pedro Friedmann Ângeli
- Angelika Keller
- Marian Brenner (ORCID: https://orcid.org/0009-0001-3781-1056)
- Martina Fischer
- Agnes Fekete
- Melina Lappe (ORCID: https://orcid.org/0009-0004-5674-2764)
- Sina Höhlein (ORCID: https://orcid.org/0009-0003-7990-6883)
- Elisabeth Jeanclos (ORCID: https://orcid.org/0000-0001-5934-5490)
- Leon Neidt (ORCID: https://orcid.org/0009-0004-1717-0214)
- Paul Wirth (ORCID: https://orcid.org/0009-0007-9698-636X)
- Arminja N. Kettenbach (ORCID: https://orcid.org/0000-0003-3979-4576)
Institutions
- Dartmouth College (US)
- University of Würzburg (DE)
- Dartmouth Psychiatric Research Center (US)
- Dartmouth Cancer Center
Publication Details
- Journal
- Science Advances
- Published
- 2026-05-29
- DOI
- https://doi.org/10.1126/sciadv.aeb2368
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Studienstiftung des Deutschen Volkes
- Julius-Maximilians-Universität Würzburg
- Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg