Title: PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance

Authors: Zhiyi Chen, Alex Inague, Kamini Kaushal, Gholamreza Fazeli, Danny Schilling, Thamara N Xavier da Silva, Ancely Ferreira dos Santos, Tasneem Cheytan, Florencio Porto Freitas, Umut Yildiz, Lucas Gasparello Viviani, Rodrigo Santiago Lima, Mikaela Peglow Pinz, Isadora Medeiros, Thais Satie Iijima, Thiago Geronimo Pires Alegria, Railmara Pereira da Silva, Larissa Regina Diniz, Simon Weinzweig, Judith Klein-Seetharaman, Andreas Trumpp, Adriana Mañas, Robert Hondal, Matthias Fischer, Christoph Bartenhagen, Briana K. Shimada, Lucia A. Seale, Thilo Samson Chillon, Marietta Fabiano, Lutz Schonburg, Ulrich Schweizer, Luis E. Netto, Flavia C. Meotti, Tobias P. Dick, Hamed Alborzinia, Sayuri Miyamoto, and José Pedro Friedmann Angeli

Abstract: Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and has traditionally been thought to begin with the uptake of the Sec carrier selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP undergoes metabolization via selenocysteine lyase (SCLY), producing selenide, a substrate used by selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor - selenophosphate (H2SePO3-) - for the biosynthesis of the selenocysteine tRNA. Here, we report the discovery of an alternative pathway mediating Sec metabolization that is independent of SCLY and mediated by peroxiredoxin 6 (PRDX6). Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the presence and functional significance of this alternative route in cancer cells where we reveal a notable association between elevated expression of PRDX6 with a highly aggressive neuroblastoma subtype. Altogether, our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering new avenues for therapeutic exploitation.

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