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Media type:
E-Article
Title:
Molecular characterization of AIFM2/FSP1 inhibition by iFSP1-like molecules
Contributor:
Xavier da Silva, Thamara Nishida;
Schulte, Clemens;
Alves, Ariane Nunes;
Maric, Hans Michael;
Friedmann Angeli, José Pedro
Published:
Springer Science and Business Media LLC, 2023
Published in:
Cell Death & Disease, 14 (2023) 4
Language:
English
DOI:
10.1038/s41419-023-05787-z
ISSN:
2041-4889
Origination:
Footnote:
Description:
AbstractFerroptosis is a form of cell death characterized by phospholipid peroxidation, where numerous studies have suggested that the induction of ferroptosis is a therapeutic strategy to target therapy refractory cancer entities. Ferroptosis suppressor protein 1 (FSP1), an NAD(P)H-ubiquinone reductase, is a key determinant of ferroptosis vulnerability, and its pharmacological inhibition was shown to strongly sensitize cancer cells to ferroptosis. A first generation of FSP1 inhibitors, exemplified by the small molecule iFSP1, has been reported; however, the molecular mechanisms underlying inhibition have not been characterized in detail. In this study, we explore the species-specific inhibition of iFSP1 on the human isoform to gain insights into its mechanism of action. Using a combination of cellular, biochemical, and computational methods, we establish a critical contribution of a species-specific aromatic architecture that is essential for target engagement. The results described here provide valuable insights for the rational development of second-generation FSP1 inhibitors combined with a tracer for screening the druggable pocket. In addition, we pose a cautionary notice for using iFSP1 in animal models, specifically murine models.