Zhu Yihao, Wang Ke, Yu Yuan, Li Xuwen, Zhai Yabo, Chen Can, Li Yajian, Wang Mingshuai, Chen Dong, Xing Nianzeng, Yang Feiya, Ye Xiongjun
Department of Urology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.
Discov Oncol. 2025 Jul 28;16(1):1429. doi: 10.1007/s12672-025-03151-5.
Circulating metabolites have been found to play an important role in the development of renal cancer, however, the specific pathways and mechanisms of their influence are still largely unknown. We aimed to investigate the role of metabolites in kidney cancer development and to explain the development of kidney cancer from a genetic perspective.
We explored the role of plasma metabolites and urinary metabolites in kidney cancer using two-sample mendelian randomization (MR) separately and validated it using multiple databases; in addition, we performed rigorous tests of pleiotropy and heterogeneity to ensure that the results were robust. Next, we explored the role of common modifiable risk factors in kidney cancer and identified the specific mechanisms by which risk factors affect kidney cancer by joint analysis of TCGA and GEO databases.
Through MR analysis, we identified six plasma metabolites and one urinary metabolite that play a major role in kidney cancer, confirmed the effects of BMI and type 1 diabetes mellitus on kidney cancer, and constructed the BMI-plasma metabolite-kidney cancer causality networks through mediated MR. In addition, we found that SLPI could significantly affect the prognosis of kidney cancer through multiple databases' joint analyses, and through multiple methods explored the pathways of SLPI's influence on kidney cancer.
In a word, this study shows that BMI can significantly increase the risk of kidney cancer, while the plasma metabolites 4-guanidinobutanoate may partially mitigate this risk, and that SLPI promotes tumorigenesis in obesity-related renal cancer by regulating protease activity.
循环代谢物已被发现在肾癌的发生发展中起重要作用，然而，其影响的具体途径和机制仍大多未知。我们旨在研究代谢物在肾癌发生中的作用，并从遗传学角度解释肾癌的发生发展。
我们分别使用两样本孟德尔随机化（MR）方法探究血浆代谢物和尿液代谢物在肾癌中的作用，并使用多个数据库进行验证；此外，我们对多效性和异质性进行了严格测试，以确保结果的稳健性。接下来，我们探究了常见可改变风险因素在肾癌中的作用，并通过对TCGA和GEO数据库的联合分析确定了风险因素影响肾癌的具体机制。
通过MR分析，我们确定了六种血浆代谢物和一种尿液代谢物在肾癌中起主要作用，证实了体重指数（BMI）和1型糖尿病对肾癌的影响，并通过中介MR构建了BMI-血浆代谢物-肾癌因果网络。此外，通过多个数据库的联合分析，我们发现分泌性白细胞蛋白酶抑制因子（SLPI）可显著影响肾癌预后，并通过多种方法探究了SLPI影响肾癌的途径。
总之，本研究表明BMI可显著增加肾癌风险，而血浆代谢物4-胍基丁酸可能部分减轻这种风险，且SLPI通过调节蛋白酶活性促进肥胖相关肾癌的肿瘤发生。
