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<p>Aerobic glycolysis supports tumor growth, but how tumor cells sense glucose to coordinate biosynthesis remains largely unclear. Here we show that in hepatocellular carcinoma cells, glucose-activated PKCε phosphorylates the purine synthesis enzyme ADSL, triggering its translocation to the endoplasmic reticulum. ADSL then promotes succination of INSIG1/2, which disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi, the activation of SREBP-1 and the transcription of downstream lipogenesis-related genes, proliferation of tumor cells, and tumorigenesis in mice. Through virtual screening, we identify Elsulfavirine, an approved HIV drug, which blocks ADSL-INSIG interaction and suppresses SREBP-1 activation induced by glucose. Combining Elsulfavirine with Lenvatinib synergistically inhibits tumor growth. Clinically, ADSL phosphorylation and INSIG succination correlate with SREBP-1 activation and poor prognosis in human HCC. In summary, these findings reveal a repurposing mechanism by which tumor cells coordinate glucose metabolism and lipogenesis via a moonlighting function of ADSL and underscore a repurposing strategy for liver cancer therapy.</p>

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INSIG1/2 succination mediated by the moonlighting function of ADSL promotes lipogenesis and liver tumorigenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月15日

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  • Yuran Duan,
  • Shuo Wang,
  • Jianyu Liu,
  • Wenxing Qin,
  • Yuli Shen,
  • Yueru Hou,
  • Xue Sun,
  • Yanni Lin,
  • Zhiqiang Hu,
  • Bofei Dong,
  • Yanli Bi,
  • Huang Yang,
  • Min Li,
  • Liwei Xiao,
  • Qingang Wu,
  • Xueli Bai,
  • Yuhao Wang,
  • Gaopeng Li,
  • Yuan Ding,
  • Zhengwei Mao,
  • Yang Luo,
  • Zhimin Lu,
  • Tong Liu,
  • Daqian Xu,
  • Shijian Liu,
  • Peng Zhan,
  • Zheng Wang

摘要

Aerobic glycolysis supports tumor growth, but how tumor cells sense glucose to coordinate biosynthesis remains largely unclear. Here we show that in hepatocellular carcinoma cells, glucose-activated PKCε phosphorylates the purine synthesis enzyme ADSL, triggering its translocation to the endoplasmic reticulum. ADSL then promotes succination of INSIG1/2, which disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi, the activation of SREBP-1 and the transcription of downstream lipogenesis-related genes, proliferation of tumor cells, and tumorigenesis in mice. Through virtual screening, we identify Elsulfavirine, an approved HIV drug, which blocks ADSL-INSIG interaction and suppresses SREBP-1 activation induced by glucose. Combining Elsulfavirine with Lenvatinib synergistically inhibits tumor growth. Clinically, ADSL phosphorylation and INSIG succination correlate with SREBP-1 activation and poor prognosis in human HCC. In summary, these findings reveal a repurposing mechanism by which tumor cells coordinate glucose metabolism and lipogenesis via a moonlighting function of ADSL and underscore a repurposing strategy for liver cancer therapy.