von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
AI Summary:
siRNA treatment is commonly associated with significant sensitization to ferroptosis, independently of the target protein knockdown.AI Topics:
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.
von Mässenhausen, Anne
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listSchlecht, Marlena Nastassja
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listBeer, Kristina
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listMaremonti, Francesca
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listTonnus, Wulf
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listBelavgeni, Alexia
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listGavali, Shubhangi
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listFlade, Karolin
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listRiley, Joel S.
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
Vringer, Esmee and Heilig, Rosalie and Riley, Joel S. and Black, Annabel and Cloix, Catherine and Skalka, George and Montes-Gómez, Alfredo E. and Aguado, Aurore and Lilla, Sergio and Walczak, Henning and Gyrd-Hansen, Mads and Murphy, Daniel J. and Huang, Danny T. and Zanivan, Sara and Tait, Stephen W.G. (2024) Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response. EMBO Journal, 43 (6). pp. 904-930. ISSN 0261-4189
Victorelli, Stella and Salmonowicz, Hanna and Chapman, James and Martini, Helene and Vizioli, Maria Grazia and Riley, Joel S. and Cloix, Catherine and Hall-Younger, Ella and Espindola-Netto, Jair Machado and Jurk, Diana and Lagnado, Anthony B. and Gomez, Lilian Sales and Farr, Joshua N. and Saul, Dominik and Reed, Rebecca and Kelly, George and Eppard, Madeline and Greaves, Laura C. and Dou, Zhixun and Pirius, Nicholas and Szczepanowska, Karolina and Porritt, Rebecca A. and Huang, Huijie and Huang, Timothy Y. and Mann, Derek A. and Masuda, Claudio Akio and Khosla, Sundeep and Dai, Haiming and Kaufmann, Scott H. and Zacharioudakis, Emmanouil and Gavathiotis, Evripidis and LeBrasseur, Nathan K. and Lei, Xue and Sainz, Alva G. and Korolchuk, Viktor I. and Adams, Peter D. and Shadel, Gerald S. and Tait, Stephen W.G. and Passos, João F. (2023) Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature, 622 (7983). pp. 627-636. ISSN 0028-0836
See full publications listZamora Gonzalez, Nadia
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listBrucker, Anne
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listBecker, Jorunn Naila
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listTmava, Mirela
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listMeyer, Claudia
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listPeitzsch, Mirko
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listHugo, Christian
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listGembardt, Florian
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listAngeli, Jose Pedro Friedmann
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listBornstein, Stefan R.
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listTait, Stephen W. G.
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listLinkermann, Andreas
Author
von Mässenhausen, Anne and Schlecht, Marlena Nastassja and Beer, Kristina and Maremonti, Francesca and Tonnus, Wulf and Belavgeni, Alexia and Gavali, Shubhangi and Flade, Karolin and Riley, Joel S. and Zamora Gonzalez, Nadia and Brucker, Anne and Becker, Jorunn Naila and Tmava, Mirela and Meyer, Claudia and Peitzsch, Mirko and Hugo, Christian and Gembardt, Florian and Angeli, Jose Pedro Friedmann and Bornstein, Stefan R. and Tait, Stephen W. G. and Linkermann, Andreas (2024) Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances, 10 (11): eadk7329. ISSN 2375-2548
See full publications listAvailable under License Creative Commons Attribution.
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