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MYCBP2-mediated HNF4α ubiquitination reprogrammed lipid metabolism in MASH-associated hepatocellular carcinoma

Oncogene volume 44, pages 1961–1974 (2025)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is a major global health burden, with metabolic dysfunction-associated steatohepatitis (MASH) emerging as a significant risk factor. The scarcity of effective pharmacological treatments for MASH and its progression to HCC underscores the need for deeper molecular insights. Our study identifies Myc-binding protein 2 (MYCBP2), an E3 ubiquitin ligase, as a potential tumor suppressor in MASH-related HCC. Through transcriptomic and proteomic analyses, we observed significant downregulation of MYCBP2 in HCC tissues. In vitro and in vivo experiments demonstrate that MYCBP2 inhibits HCC cell proliferation, migration, and invasion by modulating lipid metabolism pathways. Mechanistically, MYCBP2 promotes the ubiquitination and degradation of Hepatocyte Nuclear Factor 4 Alpha (HNF4α). This ubiquitination occurs via K33- and K48-linked polyubiquitin chains at lysines 300 and 307 of HNF4α. The results showed that MYCBP2 influences the expression of lipid metabolism-related genes and attenuates HNF4α‘s regulatory role in lipid metabolism through the mediated ubiquitination and degradation of HNF4α. Our findings elucidate the MYCBP2-HNF4α axis as a novel regulatory pathway in MASH-related HCC and highlight the broader implications of ubiquitination in cancer metabolism, offering a promising metabolic target for therapeutic intervention.

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Fig. 1: MYCBP2 is downregulated in MASH-related HCC.
Fig. 2: MYCBP2 inhibits HCC cell proliferation and invasion in vitro.
Fig. 3: MYCBP2 regulates HCC cells through lipid metabolism pathways.
Fig. 4: MYCBP2 inhibits HCC progression in vivo.
Fig. 5: MYCBP2 interacts with HNF4α to negatively regulate the expression of the HNF4α protein.
Fig. 6: MYCBP2 facilitates HNF4α degradation via ubiquitination pathway.
Fig. 7: MYCBP2 promotes HNF4α degradation via K48- and K33-linked Polyubiquitination.
Fig. 8: MYCBP2 modulates MASH-associated HCC progression through HNF4α.

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Data availability

The datasets generated and/or analyzed during the current study are included in this published article and its supplementary materials. Additional data supporting the findings of this study are available on Figshare (Figshare https://doi.org/10.6084/m9.figshare.27758889).

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Acknowledgement

We would like to express our gratitude to the teachers from the Department of Pathology at the Second Hospital of Shandong University for their assistance in this study. We also thank Freescience for providing editing services for this research.

Funding

This study was funded by the China Postdoctoral Science Foundation (Grant No. 2023M742128); the National Natural Science Foundation of China (Grant No. 82403916); the National Key Research and Development Program of China (Grant No. 2023YFF1204003) and the Shandong Provincial Natural Science Foundation (Grant No. ZR2024QH227).

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Author notes

  1. These authors contributed equally: Hao Zhang, Xiangxu Kong, Haoran Qu.

Authors and Affiliations

  1. Organ Transplant Department, Qilu Hospital of Shandong University, Jinan, China

    Hao Zhang & Bin Jin

  2. Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China

    Hao Zhang, Xiangxu Kong, Haoran Qu, Zhengyao Guan, Huaxin Zhou, Zhaoqing Yin, Kangping Lu, Xiangyu Zhai & Bin Jin

  3. The Second Clinical Medical School of Shandong University, Jinan, China

    Xiangxu Kong, Haoran Qu, Zhengyao Guan, Huaxin Zhou, Zhaoqing Yin, Kangping Lu, Xiangyu Zhai & Bin Jin

  4. Medical Integration and Practice Center, Shandong University, Jinan, China

    Yi Gao & Wei Wang

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Contributions

HZ, XXK and HRQ conceived and performed most of the experiments; YG, ZYG and ZQY accomplished some of the in vitro experiments. HXZ, KQL and WW analyzed the data. HZ, XYZ and BJ wrote the manuscript. All authors had given approval to the final version of the manuscript.

Corresponding authors

Correspondence to Wei Wang, Xiangyu Zhai or Bin Jin.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All methods in this study were performed in accordance with the relevant guidelines and regulations, including the Declaration of Helsinki for human participants and the ARRIVE guidelines for animal experiments. Ethics approval for the research involving live vertebrates (animals) was obtained from the Animal Use and Care Committee of the Second Hospital of Shandong University (License No. KYLL2024857). Ethics approval for the use of human samples and data was granted by the Scientific Research Ethics Committee of the Second Hospital of Shandong University (License No. KYLL2023413). Informed consent was obtained from all human participants prior to their inclusion in the study. No participants under the age of 18 were involved in this research. Additionally, written informed consent for the publication of identifiable images was obtained separately from all participants whose images are included in this manuscript.

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Zhang, H., Kong, X., Qu, H. et al. MYCBP2-mediated HNF4α ubiquitination reprogrammed lipid metabolism in MASH-associated hepatocellular carcinoma. Oncogene 44, 1961–1974 (2025). https://doi.org/10.1038/s41388-025-03373-5

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