PuSH - Publication Server of Helmholtz Zentrum München: Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis.

Navigation

Home

Deutsch

Research

Advanced Search

Browse by ...

... Journal

... Publication Type

... Research Data

... Publication Year

Publication overview

Support & Contact

Contact persons

Help

Data protection

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)

Publ. Version/Full Text

DOI

PMC

Abstract
Metrics
Extra information

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

Additional Metrics?

[➜Log in]

Edit extra informations Login

Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Clinical-pharmacology; Therapeutics; Necrosis; Pathway; Disease; Death; Risk

ISSN (print) / ISBN 2375-2548

e-ISSN 2375-2548

Journal Science Advances

Quellenangaben Volume: 10, Issue: 11, Article Number: eadk7329

Publisher American Association for the Advancement of Science (AAAS)

Publishing Place Washington, DC [u.a.]

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute for Pancreatic Beta Cell Research (IPI)

Grants Cancer Research UK Programme
BMBF (FERROPath consortium)
DFG
International research training group
Heisenberg-Professorship
German Research Foundation