Succinate supplementation alleviates liver cancer by inhibiting the FN1/SQLE axis-mediated cholesterol biosynthesis

作者：Shuyuan Chang, Akiko Tomii, Yunfei Zhou, Yang Xun, Yihong Dong, Jun Yan, Aodi Wu, Yumeng Wang, Qingxin Zhang, Hongxue Meng, Lei Yu, Wei Sun, Dabin Liu · 发表于：iScience · 年份：2025 · DOI：10.1016/j.isci.2024.111731 · 被引用次数：9 · 研究领域：Cancer, Lipids, and Metabolism、Cancer, Hypoxia, and Metabolism、Metabolomics and Mass Spectrometry Studies

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.