Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation

作者：Toshitaka Nakamura, Eikan Mishima, Naoya Yamada, A. Mourão, D. Trümbach, S. Doll, Jonas Wanninger, Elena Lytton, Peter Sennhenn, Thamara Nishida Xavier da Silva, J. Angeli, M. Sattler, B. Proneth, M. Conrad · 发表于：Nature Structural & Molecular Biology · 年份：2023 · DOI：10.1038/s41594-023-01136-y · 被引用次数：75 · 研究领域：Medicine

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. Extensive mutational analyses of ferroptosis suppressor protein-1 (FSP1) reveal its molecular mechanism in ferroptosis prevention and uncover the mechanism of action of the FSP1 inhibitor iFSP1 and a new species-independent FSP1 inhibitor, viFSP1.