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N6-methyadenosine-modified YWHAE mRNA promotes proliferation and inhibits ferroptosis in hepatoblastoma by mediating SLC7A11 expression

Oncogene volume 44, pages 1634–1645 (2025)Cite this article

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Abstract

Hepatoblastoma (HB) is a rare but predominant liver cancer in children, with few treatment choices in advanced stages. YWHAE is closely related to several human diseases and acts as a molecular scaffold for malignant transformation. However, whether YWHAE promotes HB development remains unknown. Conducting RNA and m6A sequencing on HB tissues, we found that YWHAE was upregulated and modified by N6-methyadenosine. Functionally, YWHAE promoted proliferation and inhibited cell death in HB by in vitro and in vivo studies. Mechanistically, METTL3-dependent m6A modification activated YWHAE mRNA expression, and the m6A reader IGF2BP2 recognized and bound to the m6A site on YWHAE mRNA, thereby enhancing the mRNA stability of YWHAE. Interestingly, RNA sequencing revealed that YWHAE knockdown was involved in regulating ferroptosis of HB cells by mediating SLC7A11 expression. Moreover, knockdown of YWHAE significantly increased the levels of lipid ROS and peroxides in HB cells, promoting the susceptibility of HB cells to ferroptosis. In summary, these findings illuminated the role of YWHAE in HB progression and uncovered its relevance to ferroptosis as a new therapeutic target for HB.

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Fig. 1: YWHAE is highly expressed in HB.
Fig. 2: YWHAE promotes HB cell proliferation in vitro and in vivo.
Fig. 3: IGF2BP2 recognizes m6A modification of YWHAE mRNA.
Fig. 4: IGF2BP2 enhances YWHAE mRNA stability via an m6A-dependent manner.
Fig. 5: IGF2BP2 promotes cell proliferation in HB.
Fig. 6: Knockdown of YWHAE inhibits SLC7A11 expression in HB cells.
Fig. 7: Knocking down YWHAE enhances the sensitivity of HB cells to ferroptosis.

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Data availability

The datasets generated during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This study was supported by the National Key Clinical Specialty Project (the construction of multidisciplinary cooperative diagnosis and treatment system for children’s cancer guided by improving clinical service capacity, 2021), the National Natural Science Foundation of China (grant number 81871727, 82072375, 82172357, 82293662, 82300037), Project of Shanghai Science and Technology Committee (grant number 23Y11907300). We acknowledge the support of all other involved investigators and participating practitioners for their valued contributions. We are indebted to all the patients and their parents and/or guardians who participated in this study. We would like to express our gratitude to EditSprings (www.editsprings.cn) for the expert linguistic services provided.

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  1. These authors contributed equally: Jiquan Zhou, Jing Wang, Liyuan Yang.

Authors and Affiliations

  1. Department of General Surgery, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai, 200127, China

    Jiquan Zhou, Jing Wang, Liyuan Yang, Tingyi Fu, Yuhua Shan, Hongxiang Gao, Chenjie Xie, Lei Zhang, Dapeng Jiang, Min Xu & Song Gu

  2. Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai, 200127, China

    Hui Li & Houshun Fang

  3. Pediatric Translational Medicine Institute and Pediatric Congenital Heart Disease Institute, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai, 200127, China

    Min Zhang

  4. Department of Laboratory Medicine, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai, 200127, China

    Ji Ma, Li Liu & Qiuhui Pan

  5. Department of International Medical, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai, 200127, China

    Song Gu

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Contributions

JZ and JW drafted the initial manuscript and performed most of the experiments. LY and TF assisted with the experiment and critical reagent preparation. HL, JM, HF, and LL provided technical help with tissue array analysis. MZ performed the bioinformatics analysis. QP and SG contributed to the experimental design, guidance, and quality control. YS, HG, CX and LZ conceived the project, analyzed the data, and finalized the figures. DJ, MX, QP and SG critically reviewed and revised the final manuscript.

Corresponding authors

Correspondence to Qiuhui Pan or Song Gu.

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The authors declare no competing interests.

Ethics approval

All methods were performed in accordance with the relevant guidelines and regulations. Animal studies were conducted under the institutional animal care and use committee of Shanghai Children’s Medical Center (SCMC-LAWEC-2022-041). Research involving human subjects received approval from the Institutional Review Board of Shanghai Children’s Medical Center, which is affiliated to Shanghai Jiao Tong University School of Medicine in China (SCMCIRB-K2023006-1). Prior to enrolling in the study, informed consent was obtained from each participant.

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Zhou, J., Wang, J., Yang, L. et al. N6-methyadenosine-modified YWHAE mRNA promotes proliferation and inhibits ferroptosis in hepatoblastoma by mediating SLC7A11 expression. Oncogene 44, 1634–1645 (2025). https://doi.org/10.1038/s41388-025-03334-y

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