Journal of affective disorders · 2026
GLDC, PYCR3, and PID1: Potential biomarkers and therapeutic targets for comorbid breast cancer and depression.
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Xu Zehui, Li Xiaofei, Sheng Jiayu, Jiang Ke
Аннотация
BACKGROUND: Triple-negative breast cancer (TNBC) and major depressive disorder (MDD) frequently co-occur, yet the shared biological mechanisms underlying this comorbidity remain poorly understood. Increasing evidence suggests that metabolic dysregulation may represent a critical link between tumor progression and depressive phenotypes.
METHODS: An integrative strategy combining metabolomics, bioinformatic analyses, and experimental validation was employed. Untargeted metabolomic profiling of brain and tumor tissues was performed in a well-established TNBC-MDD mouse model induced by 4 T1 tumor-bearing. Differentially expressed genes (DEGs) were identified from datasets of MDD (GEO) and TNBC (TCGA), followed by intersection analysis focusing on glutamine metabolism- and tricarboxylic acid (TCA) cycle-related genes. Key genes were validated by qRT-PCR and WB in both brain and tumor tissues, while candidate therapeutic agents were predicted using a drug-gene interaction network.
RESULTS: Metabolomic analysis revealed significant depletion of glutamine-related metabolites and adenosine in the TNBC-MDD comorbidity model. Transcriptomic bioinformatic analyses identified 21 DEGs shared by TNBC and MDD. Among these DEGs, those associated with core metabolic pathways were highlighted: GLDC and PYCR3 were consistently upregulated, whereas PID1 exhibited downregulation. qRT-PCR and WB validation confirmed aberrant expression of GLDC, PYCR3, and PID1 in both brain and tumor tissues. Drug prediction analysis identified several candidate compounds, including valproic acid, with potential dual therapeutic relevance for TNBC and MDD.
CONCLUSION: GLDC, PYCR3, and PID1 were identified as key metabolic regulators underlying the co-occurrence of TNBC and MDD. Their coordinated dysregulation may drive glutamine and TCA cycle reprogramming, which links peripheral malignancy to central mood dysfunction, providing a foundation for integrated therapeutic strategies.
METHODS: An integrative strategy combining metabolomics, bioinformatic analyses, and experimental validation was employed. Untargeted metabolomic profiling of brain and tumor tissues was performed in a well-established TNBC-MDD mouse model induced by 4 T1 tumor-bearing. Differentially expressed genes (DEGs) were identified from datasets of MDD (GEO) and TNBC (TCGA), followed by intersection analysis focusing on glutamine metabolism- and tricarboxylic acid (TCA) cycle-related genes. Key genes were validated by qRT-PCR and WB in both brain and tumor tissues, while candidate therapeutic agents were predicted using a drug-gene interaction network.
RESULTS: Metabolomic analysis revealed significant depletion of glutamine-related metabolites and adenosine in the TNBC-MDD comorbidity model. Transcriptomic bioinformatic analyses identified 21 DEGs shared by TNBC and MDD. Among these DEGs, those associated with core metabolic pathways were highlighted: GLDC and PYCR3 were consistently upregulated, whereas PID1 exhibited downregulation. qRT-PCR and WB validation confirmed aberrant expression of GLDC, PYCR3, and PID1 in both brain and tumor tissues. Drug prediction analysis identified several candidate compounds, including valproic acid, with potential dual therapeutic relevance for TNBC and MDD.
CONCLUSION: GLDC, PYCR3, and PID1 were identified as key metabolic regulators underlying the co-occurrence of TNBC and MDD. Their coordinated dysregulation may drive glutamine and TCA cycle reprogramming, which links peripheral malignancy to central mood dysfunction, providing a foundation for integrated therapeutic strategies.