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

  • Nat Commun. 2026 Mar 15;17(1):4002. doi: 10.1038/s41467-026-70583-0.
Yuran Duan  #  1  2  3  4 ,  Shuo Wang  #  5 ,  Jianyu Liu  #  6  7 ,  Wenxing Qin  #  8  9  10 ,  Yuli Shen  #  1  2 ,  Yueru Hou  1  2 ,  Xue Sun  6 ,  Yanni Lin  1  2 ,  Zhiqiang Hu  1  2 ,  Bofei Dong  1  2 ,  Yanli Bi  3  4 ,  Huang Yang  11 ,  Min Li  1  2 ,  Liwei Xiao  1  2 ,  Qingang Wu  1  2 ,  Xueli Bai  1 ,  Yuhao Wang  1 ,  Gaopeng Li  12 ,  Yuan Ding  3  4 ,  Zhengwei Mao  11 ,  Yang Luo  13 ,  Zhimin Lu  1  2 ,  Tong Liu  6  7 ,  Daqian Xu  14  15  16 ,  Shijian Liu  17 ,  Peng Zhan  18 ,  Zheng Wang  19  20
Affiliations
  • 1. Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
  • 2. Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Hangzhou, China.
  • 3. Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 4. Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, China.
  • 5. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China.
  • 6. Department of Oncology Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
  • 7. NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China.
  • 8. Phase I Clinical Trial Center, Department of Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 9. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 10. Department of Medical Oncology, Fudan University Shanghai Cancer Center Xiamen Hospital, Xiamen City, Fujian Province, China.
  • 11. MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, China.
  • 12. Department of Colorectal Surgery and Oncology of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 13. Department of Laboratory Medicine, Chongqing General Hospital, School of Medicine, Chongqing University, Chongqing, China.
  • 14. Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China. [email protected].
  • 15. Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Hangzhou, China. [email protected].
  • 16. NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China. [email protected].
  • 17. Department of Oncology Surgery, Harbin Medical University Cancer Hospital, Harbin, China. [email protected].
  • 18. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China. [email protected].
  • 19. Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China. [email protected].
  • 20. Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41833955 DOI: 10.1038/s41467-026-70583-0
Abstract

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.

Products