补充琥珀酸通过抑制FN1/SQLE轴介导的胆固醇生物合成来减轻肝癌。
Succinate supplementation alleviates liver cancer by inhibiting the FN1/SQLE axis-mediated cholesterol biosynthesis.
作者信息
Chang Shuyuan, Tomii Ayaka, Zhou Yunfei, Yang Xun, Dong Yihong, Yan Jun, Wu Aodi, Wang Yumeng, Zhang Qingxin, Meng Hongxue, Yu Lei, Sun Wei, Liu Dabin
机构信息
NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, The Fourth Hospital of Harbin Medical University, Harbin 15001, China.
Department of Infectious Disease, The Fourth Hospital of Harbin Medical University, Harbin 150001, China.
出版信息
iScience. 2025 Jan 2;28(2):111731. doi: 10.1016/j.isci.2024.111731. eCollection 2025 Feb 21.
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 and , highlighting its potential therapeutic applications.
琥珀酸是三羧酸循环中的一种关键代谢物，对癌症发展有促进作用。然而，外源性琥珀酸在肝细胞癌（HCC）中的作用尚不清楚。在此，我们报告，通过空间代谢组学和定量代谢组学分析确定，HCC组织中琥珀酸的浓度低于相邻正常组织。补充琥珀酸具有抗肿瘤作用，可抑制肝癌细胞的增殖和集落形成，但对非肿瘤性LO2细胞无此作用。此外，补充琥珀酸可显著减少异种移植裸鼠模型和致癌物诱导的野生型小鼠模型中的肿瘤形成。琥珀酸的抗肿瘤功能在机制上是由FN1激活的与SQLE相关的胆固醇生物合成介导的。我们的研究表明，外源性琥珀酸作为一种胆固醇生物合成抑制剂，在体内和体外均能抑制HCC，突出了其潜在的治疗应用价值。
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