Succinate supplementation alleviates liver cancer by inhibiting the FN1/SQLE axis-mediated cholesterol biosynthesis
Shuyuan Chang,
Ayaka Tomii,
Yunfei Zhou,
Xun Yang,
Yihong Dong,
Jun Yan,
Aodi Wu,
Yumeng Wang,
Qingxin Zhang,
Hongxue Meng,
Lei Yu,
Wei Sun,
Dabin Liu
Affiliations
Shuyuan Chang
NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, The Fourth Hospital of Harbin Medical University, Harbin 15001, China
Ayaka Tomii
Department of Infectious Disease, The Fourth Hospital of Harbin Medical University, Harbin 150001, China
Yunfei Zhou
NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, The Fourth Hospital of Harbin Medical University, Harbin 15001, China
Xun Yang
NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, The Fourth Hospital of Harbin Medical University, Harbin 15001, China
Yihong Dong
NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, The Fourth Hospital of Harbin Medical University, Harbin 15001, China
Jun Yan
NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, The Fourth Hospital of Harbin Medical University, Harbin 15001, China
Aodi Wu
NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, The Fourth Hospital of Harbin Medical University, Harbin 15001, China
Yumeng Wang
NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, The Fourth Hospital of Harbin Medical University, Harbin 15001, China
Qingxin Zhang
NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, The Fourth Hospital of Harbin Medical University, Harbin 15001, China
Hongxue Meng
Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China; Corresponding author
Lei Yu
Department of Infectious Disease, The Fourth Hospital of Harbin Medical University, Harbin 150001, China; Corresponding author
Wei Sun
Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China; Corresponding author
Dabin Liu
NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, The Fourth Hospital of Harbin Medical University, Harbin 15001, China; Corresponding author
Summary: Succinate is a crucial metabolite in the TCA cycle and contributes to cancer development. However, the role of exogenous succinate in hepatocellular carcinoma (HCC) is unclear. Here, we report that the concentration of succinate in HCC tissues is lower compared to adjacent normal tissues, as determined by spatial metabolomics and quantitative metabolomics analysis. Succinate supplementation exhibits an anti-tumorigenic effect, inhibiting cell proliferation and colony formation in liver cancer cells but not in non-tumor LO2 cells. Additionally, succinate supplementation significantly reduces tumor formation in xenograft nude mice models and carcinogen-induced WT mice models. The anti-tumorigenic function of succinate is mechanistically mediated by FN1-activated SQLE-related cholesterol biosynthesis. Our study demonstrates that exogenous succinate acts as a cholesterol biosynthesis inhibitor to suppress HCC both in vitro and in vivo, highlighting its potential therapeutic applications.
