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Background <p>Metabolic‒epigenetic crosstalk critically orchestrates hepatocellular carcinoma (HCC) pathogenesis. Deciphering the precise mechanism underlying epigenetic remodeling and metabolic reprogramming in HCC may lead to novel treatment paradigms, however, the key mechanisms remain elusive.</p> Methods <p>RT-qPCR, western blotting and tissue microarrary Immunohistochemistry were used to detect the expression of RasGEF domain family member 1B (RASGEF1B) in HCC and normal liver tissues. Transcriptome sequencing and high-resolution untargeted metabolomics were integrated to identify the downstream regulatory mechanism through which RASGEF1B inhibited the HCC progression. Epigenetic regulation was investigated using methylation-specific PCR and luciferase reporter assays. Bioinformatic prediction and molecular docking suggested a functional interplay among RASGEF1B, ALDH7A1, and BMI1, which was experimentally confirmed through coimmunoprecipitation, GST pull-down, and immunofluorescence assays. Protein stability and ubiquitination status of ALDH7A1 were examined using cycloheximide, immunoprecipitation assay, and an in vitro reconstituted ubiquitination system.</p> Results <p>In this study, the antitumor role of RASGEF1B was confirmed in vitro and in vivo. Transcriptomic profiling revealed that RASGEF1B overexpression significantly reduced the snail family transcriptional repressor 1 (SNAI1), a master regulator of the epithelial-mesenchymal transition. Untargeted metabolomics revealed that RASGEF1B promoted SNAI1 DNA methylation through Betaine-mediated methionine metabolic reprogramming. Further analysis confirmed that RASGEF1B competitively protected the ALDH7A1 protein from BMI1-dependent ubiquitination, thereby elevating cellular Betaine levels in HCC.</p> Conclusions <p>This study revealed that RASGEF1B inhibited SNAI1 to suppress HCC through metabolite‒epigenetic crosstalk. Our findings potentially offer a new perspective on the classical RAS signaling framework, uncovering a metabolic‒epigenetic axis as an innovative therapeutic approach for improving clinical outcomes in patients with HCC.</p> Graphical Abstract <p></p>

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RASGEF1B suppresses hepatocellular carcinoma through the ALDH7A1/Betaine/SNAI1 metabolic‒epigenetic axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月25日

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  • Zeyi Guo,
  • Kunjiang Tan,
  • Zhongzhe Li,
  • Yaguang Ren,
  • Yizhe Dai,
  • Meixian Jin,
  • Yu Fu,
  • Yukai Hu,
  • Jinhao Guo,
  • Min Zhang,
  • Chengbo Liu,
  • Shunjun Fu,
  • Feng Shen

摘要

Background

Metabolic‒epigenetic crosstalk critically orchestrates hepatocellular carcinoma (HCC) pathogenesis. Deciphering the precise mechanism underlying epigenetic remodeling and metabolic reprogramming in HCC may lead to novel treatment paradigms, however, the key mechanisms remain elusive.

Methods

RT-qPCR, western blotting and tissue microarrary Immunohistochemistry were used to detect the expression of RasGEF domain family member 1B (RASGEF1B) in HCC and normal liver tissues. Transcriptome sequencing and high-resolution untargeted metabolomics were integrated to identify the downstream regulatory mechanism through which RASGEF1B inhibited the HCC progression. Epigenetic regulation was investigated using methylation-specific PCR and luciferase reporter assays. Bioinformatic prediction and molecular docking suggested a functional interplay among RASGEF1B, ALDH7A1, and BMI1, which was experimentally confirmed through coimmunoprecipitation, GST pull-down, and immunofluorescence assays. Protein stability and ubiquitination status of ALDH7A1 were examined using cycloheximide, immunoprecipitation assay, and an in vitro reconstituted ubiquitination system.

Results

In this study, the antitumor role of RASGEF1B was confirmed in vitro and in vivo. Transcriptomic profiling revealed that RASGEF1B overexpression significantly reduced the snail family transcriptional repressor 1 (SNAI1), a master regulator of the epithelial-mesenchymal transition. Untargeted metabolomics revealed that RASGEF1B promoted SNAI1 DNA methylation through Betaine-mediated methionine metabolic reprogramming. Further analysis confirmed that RASGEF1B competitively protected the ALDH7A1 protein from BMI1-dependent ubiquitination, thereby elevating cellular Betaine levels in HCC.

Conclusions

This study revealed that RASGEF1B inhibited SNAI1 to suppress HCC through metabolite‒epigenetic crosstalk. Our findings potentially offer a new perspective on the classical RAS signaling framework, uncovering a metabolic‒epigenetic axis as an innovative therapeutic approach for improving clinical outcomes in patients with HCC.

Graphical Abstract