ArticleClinical and translational medicine2025
Targeting YBX1-m5C mediates RNF115 mRNA circularisation and translation to enhance vulnerability of ferroptosis in hepatocellular carcinoma.
Article in Clinical and translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 1 of them a synthesis that pooled it.
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Who cites it
21 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Global research status and frontiers on ferroptosis in hepatocellular carcinoma: a comprehensive bibliometric and visualized analysis.Frontiers in immunology · 2025Pooled it
- Review
- ETV4 Improves Cerebral Ischemia-Reperfusion Injury by Restraining YBX1-GPX4-Ferroptosis Cascades.Brain and behavior · 2026Article
- EvoRMD: integrating biological context and evolutionary RNA language models for interpretable prediction of RNA modifications.Genome biology · 2026Article
- mBiology direct · 2026Review
- Ferroptosis-autophagy crosstalk in bladder cancer: mechanisms and therapeutic implications.Molecular cancer · 2026Review
- YBX1 as an adaptive RNA hub in cancer: linking state-dependent RNA regulation to tumor immunity, metabolic reprogramming, and therapy resistance.Frontiers in immunology · 2026Review
- RNF145 Promotes Hepatocellular Carcinoma Metastasis through Ubiquitination and Degradation of PCDH9.Oncology research · 2026Article
- RNA Methylation in Cancer Metabolism: from Mechanisms to Therapeutic Opportunities.International journal of biological sciences · 2026Review
- Bidirectional regulation of the ubiquitin-RNA modification axis in cancer.Frontiers in oncology · 2026Review
- YBX1 Enhances the Stability of TM4SF1 in an mCombinatorial chemistry & high throughput screening · 2026Article
- NSUNs-driven dysregulation: the next frontier in targeted cancer therapy?Cell death & disease · 2025Review
- Review
- Epitranscriptomic modifications in programmed cell death: mechanistic insights and implications for liver diseases.Cellular & molecular biology letters · 2025Review
- NSUN2-mediated m5C hypermethylation ofNon-coding RNA research · 2025Article
- Transcription factor YBX1 orchestrates drug resistance and tumor progression in HCC.Drug discovery today · 2025Review
- Molecular Insights into Oxidative-Stress-Mediated Cardiomyopathy and Potential Therapeutic Strategies.Biomolecules · 2025Review
- Targeting YBX1-m5C mediates RNF115 mRNA circularisation and translation to enhance vulnerability of ferroptosis in hepatocellular carcinoma.Clinical and translational medicine · 2025Article
- Epitranscriptomic mechanisms and implications of RNA mTheranostics · 2025Review
- Recent research advances in RNA m5C methylation modification in liver diseases.Frontiers in molecular biosciences · 2025Review
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Authors and funding
18 authors.
Funding
Abstract
backgroundRNA 5-methylcytosine (m5C) plays an important role in the progression of hepatocellular carcinoma (HCC). Dysregulation of ferroptosis is closely associated with HCC. However, the effect of the epigenetic mRNA m5C modification on ferroptosis in HCC remains unclear.
methodsIn this study, ferroptosis was evaluated by detecting lipid reactive oxygen species (lipid ROS), ferrous ion and 4-hydroxynonenal (4-HNE) in xenograft mouse model, diethylnitrosamine (DEN)-initiated HCC model and so forth. The regulatory mechanisms of YBX1 in mRNA translation were elucidated using RNA sequencing, ribosome sequencing, RNA immunoprecipitation (RIP)-sequencing, bisulphite sequencing and immunoprecipitation (IP)-mass spectrometry assays. Dual-luciferase reporter, RIP-qPCR, Co-IP, RNA pulldown and methylated RNA immunoprecipitation (MeRIP)-quantitative polymerase chain reaction (qPCR) assays were performed to validate the mechanism of YBX1 in regulating mRNA translation by m5C modification.
resultsHere, we found that YBX1 promoted the translation of Ring Finger Protein 115 (RNF115) mRNA through m5C modification, thereby inhibiting ferroptosis and promoting HCC development. Moreover, RNF115 was identified as an E3 ubiquitin ligase for dihydroorotate dehydrogenase (DHODH), promoting Lys27 (K27) ubiquitination and inhibiting its autophagic degradation to counteract ferroptosis. In addition, YBX1 bound to the m5C modification sites of RNF115 3'-untranslated region (UTR) and interacted with Eukaryotic Translation Initiation Factor 4A1 (EIF4A1) to bridge the 5'-UTR regions, promoting mRNA circularisation and translation, while NOP2/Sun RNA methyltransferase 2 (NSUN2) was identified as responsible for m5C modification of RNF115 mRNA in HCC.
conclusionsThe current work revealed that YBX1 promoted RNF115 mRNA translation in an m5C-dependent manner, thereby regulating DHODH ubiquitination and expression to suppress ferroptosis. This research sheds light on the mechanism of YBX1 in m5C-modified mRNAs translation and ferroptosis, highlighting its promise as a biomarker for prognosis and a target for therapy in HCC. KEY POINTS: YBX1 inhibits ferroptosis in HCC by regulating the RNF115-DHODH axis. RNF115, an E3 ligase, mediates K27 ubiquitination and autophagic degradation of DHODH. YBX1 binds to the m5C sites of RNF115 mRNA 3'-UTR and interacts with EIF4A1 to bridge the 5'-UTR, promoting mRNA circularisation and translation. High expression of YBX1/RNF115 predicts the poor overall survival in HCC.
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