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. 2024 Dec 5;84(23):4645-4659.e9.
doi: 10.1016/j.molcel.2024.10.027. Epub 2024 Nov 14.

PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance

Zhiyi Chen  1 , Alex Inague  2 , Kamini Kaushal  3 , Gholamreza Fazeli  1 , Danny Schilling  4 , Thamara N Xavier da Silva  1 , Ancely Ferreira Dos Santos  1 , Tasneem Cheytan  3 , Florencio Porto Freitas  1 , Umut Yildiz  5 , Lucas Gasparello Viviani  6 , Rodrigo Santiago Lima  6 , Mikaela Peglow Pinz  6 , Isadora Medeiros  6 , Thais Satie Iijima  6 , Thiago Geronimo Pires Alegria  7 , Railmara Pereira da Silva  6 , Larissa Regina Diniz  6 , Simon Weinzweig  8 , Judith Klein-Seetharaman  8 , Andreas Trumpp  3 , Adriana Mañas  9 , Robert Hondal  10 , Christoph Bartenhagen  11 , Matthias Fischer  11 , Briana K Shimada  12 , Lucia A Seale  12 , Thilo Samson Chillon  13 , Marietta Fabiano  14 , Lutz Schomburg  13 , Ulrich Schweizer  14 , Luis E Netto  7 , Flavia C Meotti  6 , Tobias P Dick  4 , Hamed Alborzinia  15 , Sayuri Miyamoto  16 , José Pedro Friedmann Angeli  17
Affiliations
Free article

PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance

Zhiyi Chen et al. Mol Cell. .
Free article

Erratum in

  • PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance.
    Chen Z, Inague A, Kaushal K, Fazeli G, Schilling D, Xavier da Silva TN, Ferreira Dos Santos A, Cheytan T, Freitas FP, Yildiz U, Viviani LG, Lima RS, Pinz MP, Medeiros I, Iijima TS, Pires Alegria TG, Pereira da Silva R, Diniz LR, Weinzweig S, Klein-Seetharaman J, Trumpp A, Mañas A, Hondal R, Bartenhagen C, Fischer M, Shimada BK, Seale LA, Chillon TS, Fabiano M, Schomburg L, Schweizer U, Netto LE, Meotti FC, Dick TP, Alborzinia H, Miyamoto S, Friedmann Angeli JP. Chen Z, et al. Mol Cell. 2025 Sep 4;85(17):3343-3344. doi: 10.1016/j.molcel.2025.08.005. Epub 2025 Aug 14. Mol Cell. 2025. PMID: 40816288 No abstract available.

Abstract

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and begins with the uptake of the Sec carrier, selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP is metabolized via selenocysteine lyase (SCLY), producing selenide, a substrate for selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor, selenophosphate (H2SePO3-), for the biosynthesis of the Sec-tRNA. Here, we discovered an alternative pathway in Sec metabolism mediated by peroxiredoxin 6 (PRDX6), independent of SCLY. 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 functional significance of this alternative route in human cancer cells, revealing a notable association between elevated expression of PRDX6 and human MYCN-amplified neuroblastoma subtype. Our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering further possibilities for therapeutic exploitation.

Keywords: cancer metabolism; cell death; ferroptosis; neuroblastoma; selenium; selenocysteine metabolism.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Update of

  • PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance.
    Chen Z, Inague A, Kaushal K, Fazeli G, N Xavier da Silva T, Ferreira Dos Santos A, Cheytan T, Porto Freitas F, Yildiz U, Gasparello Viviani L, Santiago Lima R, Peglow Pinz M, Medeiros I, Geronimo Pires Alegria T, Pereira da Silva R, Regina Diniz L, Weinzweig S, Klein-Seetharaman J, Trumpp A, Manas A, Hondal R, Fischer M, Bartenhagen C, Shimada BK, Seale LA, Fabiano M, Schweizer U, Netto LE, Meotti FC, Alborzinia H, Miyamoto S, Friedmann Angeli JP. Chen Z, et al. bioRxiv [Preprint]. 2024 Jun 6:2024.06.04.597364. doi: 10.1101/2024.06.04.597364. bioRxiv. 2024. Update in: Mol Cell. 2024 Dec 5;84(23):4645-4659.e9. doi: 10.1016/j.molcel.2024.10.027. PMID: 38895225 Free PMC article. Updated. Preprint.

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