2. Academic Validation
  3. Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation

Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation

  • Nat Struct Mol Biol. 2023 Nov;30(11):1806-1815. doi: 10.1038/s41594-023-01136-y.
Toshitaka Nakamura 1,  Eikan Mishima 1 2,  Naoya Yamada 1,  André Santos Dias Mourão 3,  Dietrich Trümbach 1,  Sebastian Doll 1,  Jonas Wanninger 1,  Elena Lytton 1,  Peter Sennhenn 4,  Thamara Nishida Xavier da Silva 5,  José Pedro Friedmann Angeli 5,  Michael Sattler 3 6,  Bettina Proneth # 1,  Marcus Conrad # 7
Affiliations

Affiliations

  • 1 Institute of Metabolism and Cell Death, Molecular Target and Therapeutics Center, Helmholtz Munich, Neuherberg, Germany.
  • 2 Division of Nephrology, Rheumatology and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Japan.
  • 3 Institute of Structural Biology, Molecular Target and Therapeutics Center, Helmholtz Munich, Neuherberg, Germany.
  • 4 transMedChem, Munich, Germany.
  • 5 Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany.
  • 6 Bavarian NMR Center, Department of Bioscience, School of Natural Sciences, Technical University of Munich, Garching, Germany.
  • 7 Institute of Metabolism and Cell Death, Molecular Target and Therapeutics Center, Helmholtz Munich, Neuherberg, Germany. marcus.conrad@helmholtz-munich.de.
  • # Contributed equally.
PMID: 37957306 DOI: 10.1038/s41594-023-01136-y
Abstract

Ferroptosis, marked by iron-dependent lipid peroxidation, may present an Achilles heel for the treatment of cancers. Ferroptosis suppressor protein-1 (FSP1), as the second Ferroptosis mainstay, efficiently prevents lipid peroxidation via NAD(P)H-dependent reduction of Quinones. Because its molecular mechanisms have remained obscure, we studied numerous FSP1 mutations present in Cancer or identified by untargeted random mutagenesis. This mutational analysis elucidates the FAD/NAD(P)H-binding site and proton-transfer function of FSP1, which emerged to be evolutionarily conserved among different NADH quinone reductases. Using random mutagenesis screens, we uncover the mechanism of action of next-generation FSP1 inhibitors. Our studies identify the binding pocket of the first FSP1 inhibitor, iFSP1, and introduce the first species-independent FSP1 inhibitor, targeting the NAD(P)H-binding pocket. Conclusively, our study provides new insights into the molecular functions of FSP1 and enables the rational design of FSP1 inhibitors targeting Cancer cells.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-163002
    99.20%, FSP1 Inhibitor