Exploration of the multiomics-based mechanisms of Gancao Nourishing-Yin decoction in regulating mitochondrial metabolic genes CYB5R3 and PICK1 to influence glioma progression.

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusion: 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.