Cited by 585Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisCancer, Hypoxia, and MetabolismPulmonary Hypertension Research and Treatments

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Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis

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Xie, Na, Tan, Zheng, Banerjee, Sami, Cui, Huachun, Ge, Jing, Liu, Rui-Ming, Bernard, Karen, Thannickal, Victor J., Liu, Gang·2015·American Journal of Respiratory and Critical Care Medicine

DOI 10.1164/rccm.201504-0780ocPMC PMC4731722

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Abstract

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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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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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: Xie, Na
Tan, Zheng
Banerjee, Sami
Ge, Jing
Liu, Rui-Ming
Bernard, Karen
Thannickal, Victor J.
Liu, Gang
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
DOI: 10.1164/rccm.201504-0780oc
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
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
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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Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis

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