Stress-induced vtRNA1-1 modulates redox homeostasis and ferroptosis susceptibility in hepatocellular carcinoma cells.
4 affiliations
- 1Department for Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, Bern, 3012, Switzerland.
- 2Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital and University of Bern, Bern, 3010, Switzerland.
- 3Department for Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, Bern, 3012, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, 3012, Switzerland.
- 4Department for Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, Bern, 3012, Switzerland. Electronic address: [email protected].
Abstract
Ferroptosis is a unique form of regulated cell death characterized by iron-dependent lipid peroxidation. Although the molecular details of ferroptosis regulation have been widely explored, the contributions of short non-coding RNAs (ncRNAs) to ferroptosis regulation, other than miRNAs, remain poorly understood. Here, we identified vault RNA1-1 (vtRNA1-1) as a previously unrecognized short ncRNA regulator of ferroptosis in hepatocellular carcinoma (HCC) cells. vtRNA1-1 expression was upregulated by ferroptosis inducers and exhibited strong negative correlation with ferroptosis sensitivity, thus protecting cells from ferroptosis. vtRNA1-1 levels were elevated in selected ferroptosis-resistant cells, while its depletion reversed the phenotype thus resensitizing these cells to ferroptosis. These findings suggested a contribution of vtRNA1-1 to both intrinsic and acquired ferroptosis resistance. Mechanistically, we uncovered that increased oxidative stress, which potentiates lipid peroxidation, specifically induced expression of the vtRNA1-1 paralog in an NF-κB dependent manner. Elevated vtRNA1-1 levels suppressed NF-κB-mediated pro-oxidant gene expression, thereby limiting reactive oxygen species (ROS) accumulation and alleviating oxidative stress. Taken together, oxidative stress-inducible vtRNA1-1 governs redox balance by forming a reciprocal regulatory loop with NF-κB and this loop determines ferroptosis susceptibility by adjusting basal ROS levels. Our findings provide unprecedented insights into the regulation of redox homeostasis in HCC cells mediated by a short ncRNA and uncovered vtRNA1-1 as a potential therapeutic target for overcoming ferroptosis resistance in liver cancer.
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BibTeX
@article{kong2026stressinduced,
title = {{Stress-induced vtRNA1-1 modulates redox homeostasis and ferroptosis susceptibility in hepatocellular carcinoma cells.}},
author = {EunBin Kong and Daniel Sanchez-Taltavull and Carolina Oliveira-Rizzo and Anastasiia Suspitsyna and Deborah Stroka and Norbert Polacek},
journal = {Redox biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104439},
url = {https://europepmc.org/article/MED/42880018},
note = {CC BY},
}
RIS
TY - JOUR
TI - Stress-induced vtRNA1-1 modulates redox homeostasis and ferroptosis susceptibility in hepatocellular carcinoma cells.
AU - EunBin Kong
AU - Daniel Sanchez-Taltavull
AU - Carolina Oliveira-Rizzo
AU - Anastasiia Suspitsyna
AU - Deborah Stroka
AU - Norbert Polacek
PY - 2026
DA - 2026/10/13
JO - Redox biology
DO - 10.1016/j.redox.2026.104439
UR - https://europepmc.org/article/MED/42880018
AB - Ferroptosis is a unique form of regulated cell death characterized by iron-dependent lipid peroxidation. Although the molecular details of ferroptosis regulation have been widely explored, the contributions of short non-coding RNAs (ncRNAs) to ferroptosis regulation, other than miRNAs, remain poorly understood. Here, we identified vault RNA1-1 (vtRNA1-1) as a previously unrecognized short ncRNA regulator of ferroptosis in hepatocellular carcinoma (HCC) cells. vtRNA1-1 expression was upregulated by ferroptosis inducers and exhibited strong negative correlation with ferroptosis sensitivity, thus protecting cells from ferroptosis. vtRNA1-1 levels were elevated in selected ferroptosis-resistant cells, while its depletion reversed the phenotype thus resensitizing these cells to ferroptosis. These findings suggested a contribution of vtRNA1-1 to both intrinsic and acquired ferroptosis resistance. Mechanistically, we uncovered that increased oxidative stress, which potentiates lipid peroxidation, specifically induced expression of the vtRNA1-1 paralog in an NF-κB dependent manner. Elevated vtRNA1-1 levels suppressed NF-κB-mediated pro-oxidant gene expression, thereby limiting reactive oxygen species (ROS) accumulation and alleviating oxidative stress. Taken together, oxidative stress-inducible vtRNA1-1 governs redox balance by forming a reciprocal regulatory loop with NF-κB and this loop determines ferroptosis susceptibility by adjusting basal ROS levels. Our findings provide unprecedented insights into the regulation of redox homeostasis in HCC cells mediated by a short ncRNA and uncovered vtRNA1-1 as a potential therapeutic target for overcoming ferroptosis resistance in liver cancer.
SN - 2213-2317
ER -