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

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.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2026-03-15
DOI
https://doi.org/10.1038/s41467-026-70583-0
Primary Topic
Cancer, Hypoxia, and Metabolism
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Miaoxiu Li, Gaopeng Li, Liwei Xiao, Qingang Wu et al.
Nature Communications
Cancer, Hypoxia, and Metabolism
article

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

Miaoxiu Li, Gaopeng Li, Liwei Xiao, Qingang Wu, Bofei Dong, Yi Ding, Jianyu Liu, Yueru Hou, Yanli Bi, Yuran Duan, X. W. Sun, H. J. Yang, Zheng Wang, Yu Shen, Yanni Lin, Xueli Bai, Daqian Xu, Shijian Liu, Zhimin Lu, Wenxing Qin, Tong Liu, Zhengwei Mao, Zhiqiang Hu, Shuo Wang, Peng Zhan, Yang Luo, Yuhao Wang
article en

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.

Nature Communications
Shanghai Medical College of Fudan University (CN), Shandong University (CN), Harbin Medical University (CN), Chongqing University (CN), Fudan University Shanghai Cancer Center (CN), Third Affiliated Hospital of Harbin Medical University (CN), Blood Center of Zhejiang Province (CN), Second Affiliated Hospital of Zhejiang University (CN), First People's Hospital of Chongqing (CN), Hangzhou Cancer Hospital (CN), First Affiliated Hospital Zhejiang University (CN), Zhejiang University (CN)
Good health and well-being
Openalex Percentile: Top 21%
Cancer, Hypoxia, and Metabolism
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.