Chen Yufeng, Zhang Anjing, Lei Li, Xiao Kangping, Mao Wenchao
Department of Acupuncture and Physiotherapy, Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, Guizhou, China.
Department of Cardiology, Southern District of Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Discov Oncol. 2025 Apr 8;16(1):487. doi: 10.1007/s12672-025-02168-0.
Glioma is the most common malignancy of the central nervous system, characterised by its high invasiveness and recurrence, which significantly limit therapeutic outcomes. Energy metabolism reprogramming, especially mitochondrial dysfunction, plays a pivotal role in tumour growth, survival, and progression. Mitochondria serve as the central hub for energy production and biosynthesis, adapting through alterations in oxidative phosphorylation, lipid metabolism, and the tricarboxylic acid cycle to meet the high metabolic demands of gliomas. Gancao Nourishing-Yin (GCNY) decoction, a traditional herbal compound, has demonstrated potential antitumour effects, particularly in modulating mitochondrial metabolic pathways and oxidative stress, which are critical for tumour cell adaptation.
Genomic data from the glioma GWAS dataset in the Finnish R11 database and eQTL data from 13 distinct brain regions were analysed using Summary-data-based Mendelian Randomization(SMR) to identify glioma-associated genes. MitoCarta3.0, a database of mitochondrial genes, was used to pinpoint mitochondrial-related genes. Differentially expressed genes (DEGs) in human microglial cells treated with GCNY were extracted from the GEO dataset GSE210945 and cross-referenced with SMR results to identify key genes. Colocalisation analysis, validation using the TCGA database, survival analysis, and functional annotations of mitochondrial energy pathways were performed to explore the mechanisms of action.
Integration of SMR and MitoCarta3.0 identified 19 mitochondrial-related genes linked to gliomas, primarily involved in amino acid and fatty acid metabolism. Among these, CYB5R3 and PICK1 emerged as key genes with strong genetic links to glioma GWAS signals (PPH4 = 1). CYB5R3, upregulated in gliomas, was associated with enhanced oxidative phosphorylation, elevated reactive oxygen species (ROS) production, and poor survival outcomes (HR = 2.23, P < 0.001). PICK1, despite being downregulated, showed context-dependent roles in mitochondrial energy metabolism and tumour progression, with its high expression linked to worse prognosis (HR = 2.86, P < 0.001). PICK1 demonstrated moderate predictive capacity for one-year survival (AUC = 0.695).
This study highlights the critical roles of mitochondrial energy metabolism in glioma progression, identifying CYB5R3 and PICK1 as key regulators influenced by GCNY. By modulating mitochondrial pathways, including ROS production and oxidative phosphorylation activity, GCNY offers a novel multitarget strategy for glioma therapy. These findings underscore the importance of energy metabolism as a therapeutic target in gliomas and provide new insights into the potential of GCNY for integrated tumour management.
胶质瘤是中枢神经系统最常见的恶性肿瘤，具有高侵袭性和复发性的特点，这显著限制了治疗效果。能量代谢重编程，尤其是线粒体功能障碍，在肿瘤生长、存活和进展中起关键作用。线粒体是能量产生和生物合成的中心枢纽，通过氧化磷酸化、脂质代谢和三羧酸循环的改变进行适应，以满足胶质瘤的高代谢需求。甘草养阴（GCNY）汤是一种传统草药复方，已显示出潜在的抗肿瘤作用，特别是在调节对肿瘤细胞适应至关重要的线粒体代谢途径和氧化应激方面。
使用基于汇总数据的孟德尔随机化（SMR）分析芬兰R11数据库中胶质瘤全基因组关联研究（GWAS）数据集的基因组数据和来自13个不同脑区的表达定量性状位点（eQTL）数据，以识别胶质瘤相关基因。线粒体基因数据库MitoCarta3.0用于确定线粒体相关基因。从基因表达综合数据库（GEO）数据集GSE210945中提取用GCNY处理的人小胶质细胞中的差异表达基因（DEG），并与SMR结果交叉参考以识别关键基因。进行共定位分析、使用癌症基因组图谱（TCGA）数据库进行验证、生存分析以及线粒体能量途径的功能注释，以探索其作用机制。
SMR和MitoCarta3.0的整合确定了19个与胶质瘤相关的线粒体相关基因，主要参与氨基酸和脂肪酸代谢。其中，细胞色素b5还原酶3（CYB5R3）和蛋白相互作用C激酶1（PICK1）成为与胶质瘤GWAS信号有强遗传联系的关键基因（后验概率PPH4 = 1）。CYB5R3在胶质瘤中上调，与氧化磷酸化增强、活性氧（ROS）产生增加和不良生存结果相关（风险比HR = 2.23，P < 0.001）。PICK1尽管下调，但在 mitochondrial能量代谢和肿瘤进展中显示出依赖背景的作用，其高表达与更差的预后相关（HR = 2.86，P < 0.001）。PICK1对一年生存率具有中等预测能力（曲线下面积AUC = 0.695）。
本研究强调了线粒体能量代谢在胶质瘤进展中的关键作用，确定CYB5R3和PICK1为受GCNY影响的关键调节因子。通过调节包括ROS产生和氧化磷酸化活性在内的线粒体途径，GCNY为胶质瘤治疗提供了一种新的多靶点策略。这些发现强调了能量代谢作为胶质瘤治疗靶点的重要性，并为GCNY在综合肿瘤管理中的潜力提供了新的见解。
