INSIG1/2 succination mediated by the moonlighting function of ADSL promotes lipogenesis and liver tumorigenesis
Year: 2026
Type: article
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. Cancer cells could sense the availability of glucose to coordinate macromolecular synthetic processes. Here the authors find that glucose-activated adenylosuccinate lyase (ADSL) possesses a moonlighting function of promoting protein succination, thereby upregulating lipogenesis in hepatocellular carcinoma cells.
Source: Nature Communications
Authors: 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
Institutions: Second Affiliated Hospital of Zhejiang University, First Affiliated Hospital Zhejiang University, Zhejiang University, Shandong University, Harbin Medical University, Third Affiliated Hospital of Harbin Medical University, Shanghai Medical College of Fudan University, Fudan University, Fudan University Shanghai Cancer Center, Chongqing University
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W7136089595