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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

Abstract

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.

Details

Original languageEnglish
Article numbereadk7329
Pages (from-to)eadk7329
JournalScience advances
Volume10
Issue number11
Publication statusPublished - 15 Mar 2024
Peer-reviewedYes

External IDs

PubMedCentral PMC10942120
Scopus 85188201656
ORCID /0000-0001-8893-5326/work/173988545
ORCID /0000-0003-2739-345X/work/173988827
ORCID /0000-0001-6287-9725/work/173988898
ORCID /0000-0002-9728-1413/work/173989015

Keywords

Keywords

  • Humans, Signal Transduction, RNA, Small Interfering/genetics, Ferroptosis/genetics, Up-Regulation, Transcription Factors/metabolism