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Background <p>Portal vein tumor thrombus is a lethal complication of HCC for which effective biomarkers are urgently needed.</p> Methods <p>Through proteomic profiling, functional and mechanistic assays, and machine learning-based evaluation of serum NSUN6 in 472 HCC patients with external validation (<i>n</i> = 98), we characterized an epitranscriptomic regulator of HCC metastasis.</p> Results <p>NSUN6 was downregulated in PVTT and suppressed metastasis by catalyzing m⁵C modification of <i>SAV1</i> mRNA, stabilizing its transcript and activating Hippo signaling. Furthermore, NSUN6 was released from HCC cells via extracellular vesicle-associated and non-canonical pathways. Circulating NSUN6 levels were inversely associated with metastasis in both discovery and validation cohorts, and lower levels predicted shorter metastasis-free survival.</p> Conclusion <p>Our findings establish the NSUN6–SAV1–YAP axis as a key epitranscriptomic tumor-suppressive mechanism and support circulating NSUN6 as a potential biomarker for early risk stratification in HCC.</p>

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Circulating NSUN6 serves as a prognostic biomarker for early metastasis in HCC via hippo pathway modulation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月17日

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  • Xutong Li,
  • Honghai Xu,
  • Yu Chang,
  • Yani Zhang,
  • Hui Xu,
  • Xin Yin,
  • Wanxiang Zhang,
  • Yi Luo,
  • Wanting Lu,
  • Wenhu Fan,
  • Wanwan Ruan,
  • Jiapei Shen,
  • Zhenxing Li,
  • Shucheng Du,
  • Lutterodt Bentum-Ennin,
  • Jing Ni,
  • Wei Gao,
  • Jiabin Li,
  • Wanglai Hu,
  • Wanshui Yang,
  • Yufeng Gao,
  • Hao Gu

摘要

Background

Portal vein tumor thrombus is a lethal complication of HCC for which effective biomarkers are urgently needed.

Methods

Through proteomic profiling, functional and mechanistic assays, and machine learning-based evaluation of serum NSUN6 in 472 HCC patients with external validation (n = 98), we characterized an epitranscriptomic regulator of HCC metastasis.

Results

NSUN6 was downregulated in PVTT and suppressed metastasis by catalyzing m⁵C modification of SAV1 mRNA, stabilizing its transcript and activating Hippo signaling. Furthermore, NSUN6 was released from HCC cells via extracellular vesicle-associated and non-canonical pathways. Circulating NSUN6 levels were inversely associated with metastasis in both discovery and validation cohorts, and lower levels predicted shorter metastasis-free survival.

Conclusion

Our findings establish the NSUN6–SAV1–YAP axis as a key epitranscriptomic tumor-suppressive mechanism and support circulating NSUN6 as a potential biomarker for early risk stratification in HCC.