ArticleRedox biology2025
c-Myc promotes metabolic reprogramming in pulmonary hypertension via the stimulation of glutaminolysis and the reductive tricarboxylic acid cycle.
Article in Redox biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
6 citing papers in PubMed.
- Hyperuricemia and Hypoxic Pulmonary Hypertension: Pathogenic Links, Clinical Evidence, and Emerging Therapeutic Insights.Cardiovascular drugs and therapy · 2026Review
- MYC in Oncogenesis and Therapeutic Implications.MedComm · 2026Review
- Post-translational modification crosstalk in pulmonary arterial hypertension: mechanisms and therapeutic implications.Molecular biology reports · 2026Review
- Pulmonary Hypertension Molecular Switch: HIF Signaling Pathway.Pulmonary circulation · 2026Review
- Purine metabolic adaptation protects the endothelium from disturbed flow-induced DNA damage and atherosclerosis.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Convergent hub pathways targeted by IAV, SARS-CoV-2, and RSV in type II alveolar epithelial cells: molecular mechanisms and therapeutic implications.Frontiers in immunology · 2026Review
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
Endothelial cell (EC) dysfunction is key in initiating and progressing pulmonary hypertension (PH). EC dysfunction in PH leads to hyperproliferation and vascular remodeling of the pulmonary blood vessels. Increased glutaminolysis and altered cellular metabolism are pivotal in hyperproliferative cancer cells. However, whether a similar enhancement in glutamine metabolism is involved in the EC hyperproliferation and if this contributes to vascular remodeling during PH development is unresolved and was the focus of our study. Metabolic flux analysis showed elevated glutaminolysis and enhanced metabolic flux through the reductive tricarboxylic acid (TCA) cycle in pulmonary arterial ECs isolated from an ovine experimental model of PH (PH-PAECs). PH-PAECs also exhibited increased c-Myc protein levels, a master regulator of glutaminolysis. Therefore, we assessed the effect of increased c-Myc expression on metabolic reprogramming, glutaminolysis, and proliferation in control PAECs. Results from a comprehensive snapshot metabolomics investigation and metabolic flux analysis confirmed the reprogramming of mitochondrial metabolism, enhanced glutamine metabolism, and increased glycolysis in c-Myc overexpressing PAECs. Additionally, c-Myc overexpression impacted the ATP production rate, disrupted mitochondrial respiration, increased reactive oxygen species production, induced cell proliferation, and suppressed apoptosis. Functionally, these metabolic changes suppressed nitric oxide (NO) production. We also demonstrate that a small-molecule c-Myc inhibitor, 10058-F4, attenuates glutaminolysis, suppresses the reverse TCA cycle and glycolysis, and reverses the hyperproliferative phenotype, thereby restoring NO levels in PH-PAECs. We also demonstrate that directly targeting HIF-1α reverses the hyper-proliferative, anti-apoptotic phenotype in PH-PAECs. Thus, targeting c-Myc signaling and suppressing glutaminolysis or glycolysis could be a novel therapy for PH.
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Registered trials
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