Targeting YBX1-m5C mediates RNF115 mRNA circularisation and translation to enhance vulnerability of ferroptosis in hepatocellular carcinoma

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-03-15 DOI:10.1002/ctm2.70270

Ouwen Li, Ke An, Han Wang, Xianbin Li, Yueqin Wang, Lan Huang, Yue Du, Nuo Qin, Jiasheng Dong, Jingyao Wei, Ranran Sun, Yong Shi, Yanjia Guo, Xiangyi Sun, Ying Yang, Yun-Gui Yang, Quancheng Kan, Xin Tian

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Abstract

Background

RNA 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.

Methods

In 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.

Results

Here, 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.

Conclusions

The 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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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.