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Single-cell sequencing and spatial transcriptomics reveal the evolution of glucose metabolism in hepatocellular carcinoma and identify G6PD as a potential therapeutic target

癌变 转录组 癌症研究 肝细胞癌 生物 下调和上调 细胞生长 细胞 比例危险模型 代谢组学 计算生物学 癌症 医学 生物信息学 基因 内科学 基因表达 遗传学
作者
Deyang Xi,Yinshuang Yang,Jiayi Guo,Mengjiao Wang,Xuebing Yan,Chunyang Li
出处
期刊:Frontiers in Oncology [Frontiers Media]
卷期号:15
标识
DOI:10.3389/fonc.2025.1553722
摘要

Background Glucose metabolism reprogramming provides significant insights into the development and progression of malignant tumors. This study aims to explore the temporal-spatial evolution of the glucose metabolism in HCC using single-cell sequencing and spatial transcriptomics (ST), and validates G6PD as a potential therapeutic target for HCC. Methods We collected single-cell sequencing data from 7 HCC and adjacent non-cancerous tissues from the GSE149614 database, and ST data from 4 HCC tissues from the HRA000437 database. Pseudotime analysis was performed on the single-cell data, while ST data was used to analyze spatial metabolic activity. High-throughput sequencing and experiments, including wound healing, CCK-8, and transwell assays, were conducted to validate the role and regulatory mechanisms of G6PD in HCC. Results Our study identified a progressive upregulation of PPP-related genes during tumorigenesis. ST analysis revealed elevated PPP metabolic scores in the central and intermediate tumor regions compared to the peripheral zones. High-throughput sequencing and experimental validation further suggested that G6PD-mediated regulation of HCC cell proliferation, migration, and invasion is likely associated with glutathione metabolism and ROS production. Finally, Cox regression analysis cofirmed G6PD as an independent prognostic factor for overall survival in HCC patients. Conclusion Our study provides novel insights into the changes in glucose metabolism in HCC from both temporal and spatial perspectives. We experimentally demonstrated that G6PD regulates proliferation, migration, and invasion in HCC and propose G6PD as a prognostic marker and therapeutic metabolic target for the HCC.
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