2026/03/31 by EunBin Kong, Daniel Sanchez-Taltavull, Carolina Oliveira Rizzo +3 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Cancer-related molecular mechanisms research #Ferroptosis and cancer prognosis #RNA modifications and cancer
paper · pdf · doi:10.64898/2026.03.30.715395
openalex publication_date 2026/03/31 · openalex created_date 2026/04/02 · openalex updated_date 2026/07/14
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.