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Takashima, H.* ; Makino, R.* ; Taguchi, H.* ; Ito, J. ; Mishima, E. ; Takenaka, Y.* ; Akiyama, Y.* ; Sumi, D.* ; Conrad, M. ; Tomikoka, Y.* ; Toyama, T.* ; Saito, Y.*

Arsenite sensitizes to ferroptosis by disrupting selenium metabolism and reducing GPx4 expression.

Toxicology 522:154409 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Arsenic (As), an environmental toxicant commonly found in groundwater, exerts its toxic effects primarily through oxidative stress. Selenium (Se) plays a crucial role in counteracting oxidative stress by promoting the synthesis of Se-containing antioxidant enzymes, such as glutathione peroxidases (GPx). To elucidate the impact of As on cellular Se metabolism, we investigated the effects of inorganic arsenic on cultured cells (HT-1080, Jurkat, and SH-SY5Y). Our findings indicate that As(III) disrupts Se metabolism and inhibits Se-induced GPx expression. By comparing different Se sources (selenoprotein P, selenocysteine, and selenite), we determined that As(III) primarily interferes with Se metabolism downstream of selenite, an inorganic form of Se. Notably, exposure to As(III) reduced Se incorporation into RNA, suggesting inhibition of Sec-tRNASec synthesis, a critical step in selenoprotein biosynthesis. Additionally, As(III) increased cellular susceptibility to ferroptosis, a form of oxidative stress-driven lipid peroxidation-mediated cell death primarily regulated by GPx4. Supporting this, genetic deletion of PRDX6, a recently identified regulator of cellular Se metabolism, further suppressed selenoprotein expression and exacerbated As(III)-induced ferroptosis. These findings provide new insights into the toxicological mechanisms of As compounds, highlighting their role in disrupting Se metabolism and potentially mitigating the side effects associated with arsenic-based anticancer therapies.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Arsenic ; Ferroptosis ; Glutathione Peroxidase ; Peroxiredoxin 6 ; Selenium ; Vitamin E; Selenoprotein-p; Protein
ISSN (print) / ISBN 0300-483X
e-ISSN 0300-483X
Zeitschrift Toxicology
Quellenangaben Band: 522, Heft: , Seiten: , Artikelnummer: 154409 Supplement: ,
Verlag Elsevier
Verlagsort Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
Förderungen Tohoku University 2025 Open Access Promotion APC Support Program
Frontier Research in Duo (FRiD) , Tohoku Univ, TT
JSPS KAKENHI