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Integrating multi-omics approaches reveals metabolic reprogramming and identifies PDHX as a candidate node in
Quancheng Yang1,2, Siqi Chen1,2, Mengjia Sun1,2
1Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Introduction:
Metabolic reprogramming is a central driver of malignant progression in non-small cell lung cancer (NSCLC). However, conventional targeted therapies face significant limitations due to drug resistance and narrow therapeutic windows. Triptolide, a natural tricyclic diterpenoid derived from Tripterygium wilfordii, exhibits potent antitumor activity, yet its precise mechanisms for modulating metabolic reprogramming in NSCLC remain elusive.
Methods:
Using NSCLC cell models, we assessed TPL effects on proliferation, migration, and mitochondrial function via CCK-8, Transwell, ROS, and MMP assays. In vivo efficacy was evaluated in xenograft models. Untargeted metabolomics identified metabolic alterations, while DARTS proteomics screened for potential TPL-interacting proteins.
Results:
TPL significantly inhibited NSCLC cell proliferation and induced metabolic alterations characterized by glycolytic suppression (HK2 downregulation) and concurrent disruption of mitochondrial oxidative phosphorylation (OXPHOS)-associated proteins. Metabolomics revealed systemic metabolic shifts, with pyruvate metabolism and glutathione pathways being most significantly altered. Mechanistically, multi-omics analysis identified PDHX as a key node within a broader metabolic network disrupted by TPL, associated with glycolytic suppression (via HK2 degradation) and mitochondrial dysfunction.
Conclusion:
These findings suggest that TPL exerts antitumor effects in NSCLC by disrupting both glycolysis and mitochondrial function, with PDHX identified as a candidate mediator. Further studies are warranted to explore its therapeutic potential.
Insights
Triptolide inhibits non-small cell lung cancer (NSCLC) by disrupting glycolysis and mitochondrial function. This natural compound, Triptolide, shows promise by targeting key metabolic pathways and proteins like PDHX in NSCLC treatment.
Area of Science:
- Oncology
- Metabolic pathways
- Drug discovery
Background:
- Metabolic reprogramming drives non-small cell lung cancer (NSCLC) progression.
- Targeted therapies for NSCLC are limited by drug resistance.
- Triptolide (TPL) shows antitumor activity, but its mechanisms in NSCLC are unclear.
Purpose of the Study:
- To investigate the mechanisms by which Triptolide (TPL) modulates metabolic reprogramming in non-small cell lung cancer (NSCLC).
- To assess the effects of TPL on NSCLC cell proliferation, migration, and mitochondrial function.
- To identify potential TPL-interacting proteins and metabolic targets in NSCLC.
Main Methods:
- NSCLC cell models were used to evaluate TPL effects on proliferation, migration, and mitochondrial function via CCK-8, Transwell, ROS, and MMP assays.
- In vivo efficacy was assessed in xenograft models.
- Untargeted metabolomics and DARTS proteomics were employed to identify metabolic alterations and potential TPL-binding proteins.
Main Results:
- TPL significantly inhibited NSCLC cell proliferation and induced metabolic alterations, including glycolytic suppression (HK2 downregulation) and disrupted mitochondrial oxidative phosphorylation (OXPHOS).
- Metabolomics revealed significant alterations in pyruvate metabolism and glutathione pathways.
- Multi-omics analysis identified PDHX as a key node disrupted by TPL, mediating glycolytic suppression and mitochondrial dysfunction.
Conclusions:
- TPL exerts antitumor effects in NSCLC by disrupting both glycolysis and mitochondrial function.
- PDHX is identified as a potential mediator of TPL's effects in NSCLC.
- Further research into TPL's therapeutic potential for NSCLC is warranted.
