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Background <p>Hepatocellular carcinoma (HCC), the most common form of liver cancer, presents a challenging malignancy with scarce treatment options. Liver progenitor cells (LPCs) play a pivotal role in both liver regeneration and the progression of liver cancer, yet the specific functions of LPCs from different origins in liver cancer remain to be fully elucidated.</p> Methods <p>We explored the liver progenitor-like cells derived from human hepatocytes (HepLPCs) on the proliferation of HCC both in vitro and in vivo. The mitochondrial function was assessed through electron microscopy and functional experiments. Transcriptomic sequencing and western blot unveiled the fundamental mechanisms at play, whereas metabolomic sequencing pinpointed crucial effector molecules involved in the paracrine secretion of HepLPCs.</p> Results <p>By employing a co-culture system of HepLPCs and HCC cells, we found that HepLPCs markedly inhibited HCC growth by prompting mitochondrial dysfunction, which further led to the co-inhibition of the Notch1 and JAK1/STAT3 signaling pathways through paracrine actions involving S-adenosylmethionine (SAM) and Nicotinic acid (NA).</p> Conclusions <p>This study has uncovered that HepLPCs have a suppressive influence on the proliferation of HCC cells. This is achieved through the impairment of mitochondrial function and the inhibition of key signaling pathways, namely, Notch1 and JAK1/STAT3, which are critical drivers of cancer progression. The secretion of the metabolites SAM and NA by HepLPCs appears to be instrumental in mediating these effects. These findings provide a solid foundation for identifying new therapeutic targets and clarifying the mechanisms through which HepLPCs can be harnessed to effectively treat HCC.</p>

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Inhibition of liver cancer cell growth by metabolites S-adenosylmethionine and nicotinic acid originating from liver progenitor cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月28日

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  • Wen-Ming Liu,
  • Cai-Yang Chen,
  • Hong-Qian Ma,
  • Qiu-Qiu Zhang,
  • Xu Zhou,
  • Yu-Ling Wu,
  • Wei-Jian Huang,
  • Xiao-Shu Qi,
  • Yu-Xin Zhang,
  • Dan Tang,
  • Han-Yong Sun,
  • Hong-Ping Wu,
  • Ying-Fu Jiao,
  • Zhi-Ying He,
  • Wei-Feng Yu,
  • He-Xin Yan

摘要

Background

Hepatocellular carcinoma (HCC), the most common form of liver cancer, presents a challenging malignancy with scarce treatment options. Liver progenitor cells (LPCs) play a pivotal role in both liver regeneration and the progression of liver cancer, yet the specific functions of LPCs from different origins in liver cancer remain to be fully elucidated.

Methods

We explored the liver progenitor-like cells derived from human hepatocytes (HepLPCs) on the proliferation of HCC both in vitro and in vivo. The mitochondrial function was assessed through electron microscopy and functional experiments. Transcriptomic sequencing and western blot unveiled the fundamental mechanisms at play, whereas metabolomic sequencing pinpointed crucial effector molecules involved in the paracrine secretion of HepLPCs.

Results

By employing a co-culture system of HepLPCs and HCC cells, we found that HepLPCs markedly inhibited HCC growth by prompting mitochondrial dysfunction, which further led to the co-inhibition of the Notch1 and JAK1/STAT3 signaling pathways through paracrine actions involving S-adenosylmethionine (SAM) and Nicotinic acid (NA).

Conclusions

This study has uncovered that HepLPCs have a suppressive influence on the proliferation of HCC cells. This is achieved through the impairment of mitochondrial function and the inhibition of key signaling pathways, namely, Notch1 and JAK1/STAT3, which are critical drivers of cancer progression. The secretion of the metabolites SAM and NA by HepLPCs appears to be instrumental in mediating these effects. These findings provide a solid foundation for identifying new therapeutic targets and clarifying the mechanisms through which HepLPCs can be harnessed to effectively treat HCC.