PuSH - Publikationsserver des Helmholtz Zentrums München

von Mässenhausen, A.* ; Schlecht, M.N.* ; Beer, K.* ; Maremonti, F.* ; Tonnus, W.* ; Belavgeni, A.* ; Gavali, S.* ; Flade, K.* ; Riley, J.S.* ; Zamora Gonzalez, N.* ; Brucker, A.J.* ; Becker, J.N.* ; Tmava, M.* ; Meyer, C.* ; Peitzsch, M.* ; Hugo, C.* ; Gembardt, F.* ; Angeli, J.P.F.* ; Bornstein, S.R. ; Tait, S.W.G.* ; Linkermann, A.*

Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis.

Sci. Adv. 10:eadk7329 (2024)
Verlagsversion DOI PMC
Creative Commons Lizenzvertrag
Small interfering RNAs (siRNAs) are widely used in biomedical research and in clinical trials. Here, we demonstrate that siRNA treatment is commonly associated with significant sensitization to ferroptosis, independently of the target protein knockdown. Genetically targeting mitochondrial antiviral-signaling protein (MAVS) reversed the siRNA-mediated sensitizing effect, but no activation of canonical MAVS signaling, which involves phosphorylation of IkBα and interferon regulatory transcription factor 3 (IRF3), was observed. In contrast, MAVS mediated a noncanonical signal resulting in a prominent increase in mitochondrial ROS levels, and increase in the BACH1/pNRF2 transcription factor ratio and GPX4 up-regulation, which was associated with a 50% decrease in intracellular glutathione levels. We conclude that siRNAs commonly sensitize to ferroptosis and may severely compromise the conclusions drawn from silencing approaches in biomedical research. Finally, as ferroptosis contributes to a variety of pathophysiological processes, we cannot exclude side effects in human siRNA-based therapeutical concepts that should be clinically tested.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Clinical-pharmacology; Therapeutics; Necrosis; Pathway; Disease; Death; Risk
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Zeitschrift Science Advances
Quellenangaben Band: 10, Heft: 11, Seiten: , Artikelnummer: eadk7329 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort Washington, DC [u.a.]
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Pancreatic Beta Cell Research (IPI)
Förderungen Cancer Research UK Programme
BMBF (FERROPath consortium)
DFG
International research training group
Heisenberg-Professorship
German Research Foundation