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Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis
Open accessAbstract
Rationale: Dysregulation of cellular metabolism has been shown to participate in several pathologic processes. However, the role of metabolic reprogramming is not well appreciated in the pathogenesis of organ fibrosis. Objectives: To determine if glycolytic reprogramming participates in the pathogenesis of lung fibrosis and assess the therapeutic potential of glycolytic inhibition in treating lung fibrosis. Methods: A cell metabolism assay was performed to determine glycolytic flux and mitochondrial respiration. Lactate levels were measured to assess glycolysis in fibroblasts and lungs. Glycolytic inhibition by genetic and pharmacologic approaches was used to demonstrate the critical role of glycolysis in lung fibrosis. Measurements and Main Results: Augmentation of glycolysis is an early and sustained event during myofibroblast differentiation, which is dependent on the increased expression of critical glycolytic enzymes, in particular, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Augmented glycolysis contributes to the stabilization of hypoxia-inducible factor 1-α, a master regulator of glycolytic enzymes implicated in organ fibrosis, by increasing cellular levels of tricarboxylic acid cycle intermediate succinate in lung myofibroblasts. Inhibition of glycolysis by the PFKFB3 inhibitor 3PO or genomic disruption of the PFKFB3 gene blunted the differentiation of lung fibroblasts into myofibroblasts, and attenuated profibrotic phenotypes in myofibroblasts isolated from the lungs of patients with idiopathic pulmonary fibrosis. Inhibition of glycolysis by 3PO demonstrates therapeutic benefit in bleomycin-induced and transforming growth factor-β1–induced lung fibrosis in mice. Conclusions: Our data support the novel concept of glycolytic reprogramming in the pathogenesis of lung fibrosis and provide proof-of-concept that targeting this pathway may be efficacious in treating fibrotic disorders, such as idiopathic pulmonary fibrosis.
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“Furthermore, monocytes and macrophages are capable of remarkable functional plasticity, displaying diverse phenotypes during wound healing dependent on multiple cues including the environmental niche61,62 and the temporal stage of tissue injury and repair63–66.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [62]
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“Glycolytic reprogramming has been shown to play an important role in the pathogenesis of lung fibrosis, with higher glycolytic activity detected in fibrotic areas (143).”
From Aging and Lung Disease (2020) · cites this paper as [143]
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Research works printed but not linked: 1
- Xie, 2015, Glycolytic reprogramming is required for myofibroblast differentiation and lung fibrosis [abstract], Am J Respir Crit Care Med, 191, A4922
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Metadata
- Authors
- Xie, N., Tan, Z., Banerjee, S., Cui, H., Ge, J., Liu, R.-M., Bernard, K., Thannickal, V. J., & Liu, G.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Liu, Gang
- ORCID
- Venue
- American Journal of Respiratory and Critical Care Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-12
- Volume
- 192
- Issue
- 12
- Pages
- 1462-1474
- ISSN
- 1073-449X (ISSN-L)
- 1535-4970
- PMC
- PMC4731722
- OpenAlex
- W1793883704
- Cited by
- 582
- References
- 57
- Citations by year
- 2026: 60 · 2025: 67 · 2024: 75 · 2023: 89 · 2022: 63 · 2021: 78 · 2020: 47 · 2019: 34 · 2018: 30 · 2017: 25 · 2016: 10 · 2015: 3
- FWCI
- 17.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Respiratory and Critical Care Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 076206, HL114470, HL-105473, R01HL105473, R01HL076206, P01HL114470)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Keywords
- glycolytic reprogramming, pulmonary fibrosis, myofibroblast differentiation, PFKFB3, 3PO, hypoxia-inducible factor-1α, succinic acid, cellular metabolism, idiopathic pulmonary fibrosis, bleomycin-induced fibrosis, TGF-β1, glycolysis inhibition, fibroblasts
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Disease Models, Animal, Glycolysis, Humans, Lung, Mice, Inbred C57BL, Mice, Idiopathic Pulmonary Fibrosis, Myofibroblasts
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