Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation
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// Beatriz Ballester 1 , 2 , * , Javier Milara 1 , 2 , 3 , 4 , * and Julio Cortijo 1 , 2 , 5 1 Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain 2 CIBERES, Health Institute Carlos III, Valencia, Spain 3 Health Research Institute INCLIVA, Valencia, Spain 4 Pharmacy Unit, Clinic University Hospital, Valencia, Spain 5 Research and Teaching Unit, University General Hospital Consortium, Valencia, Spain * These authors contributed equally to this work Correspondence to: Beatriz Ballester, email: beaballester7@gmail.com Javier Milara, email: xmilara@hotmail.com Keywords: pirfenidone; idiopathic pulmonary fibrosis; MUC1; transforming growth factor beta-1; fibroblasts Received: December 11, 2019 Accepted: March 03, 2020 Published: April 14, 2020 ABSTRACT Pirfenidone is a pleiotropic molecule approved to treat idiopathic pulmonary fibrosis (IPF). Pirfenidone has demonstrated to downregulate transforming growth factor-β1 (TGF-β1) cellular effects. However, its anti-fibrotic mechanism remains unclear. Here, we aim to analyze the effects of pirfenidone on the TGF-β1 canonical and non-canonical pathways, as well as, on the most characteristic IPF cellular processes. Results observed in this work showed that TGF-β1-induced canonical SMAD3 and non-canonical ERK1/2 phosphorylations were not inhibited by pirfenidone in alveolar A549 and lung fibroblasts MRC5 cells. In contrast, pirfenidone inhibited TGF-β1-induced MUC1-CT Thr 41 (1224) and Tyr 46 (1229) phosphorylations, thus reducing the β-catenin activation. Additionally, immunoprecipitation and immunofluorescence studies in ATII cells and lung fibroblasts showed that pirfenidone inhibited the formation and nuclear translocation of the transcriptional fibrotic TGF-β1-induced phospho-SMAD3/MUC1-CT/active-β-catenin complex, and consequently the SMAD-binding element activation (SBE). This study provided also evidence of the inhibitory effect of pirfenidone on the TGF-β1-induced ATII to mesenchymal and fibroblast to myofibroblast transitions, fibroblast proliferation and ATII and fibroblast senescence. Therefore, it indicates that pirfenidone’s inhibitory effect on TGF-β1-induced fibrotic cellular processes is mediated by the inhibition of MUC1-CT phosphorylation, β-catenin activation, nuclear complex formation of phospho-SMAD3/MUC1-CT/active β-catenin and SBE activation, which may be of value to further develop anti-fibrotic IPF therapies.
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Pirfenidone is a small molecule that modulates fibrotic and inflammatory pathways, including TGF-beta and TNF-alpha.
“Pirfenidone is a small molecule that modulates fibrotic and inflammatory pathways, including TGF-β and TNF-α.9,10”
From Deupirfenidone Compared with Pirfenidone and Placebo in Idiopathic Pulmonary Fibrosis (ELEVATE-IPF): a Phase 2b Randomized Placebo-Controlled Trial (2026) · cites this paper as [9]
The Introduction and Discussion describe pirfenidone as an anti-fibrotic, anti-inflammatory molecule that downregulates TGF-β1 cellular effects. The Results also report inhibition of specific TGF-β1-induced fibrotic processes. Our copy does not address modulation of TNF-α, so that part of the claim is not supported. (LLM, conf=0.87)
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Pharmacological frontiers in senescence: Transforming senescence with drug repurposing
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Beck, L., Pinilla, E., Arcanjo, D. D. R., Hernanz, R., Prat‐Duran, J., Petersen, A. G., Köhler, R., Sheykhzade, M., Comerma-Steffensen, S., & Simonsen, U. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.619152 · Cited by 5 · see citing works
Maher, T. M., Hamblin, M. J., Choi, W.-I., Case, A. H., Tomos, I. P., Tzouvelekis, A. E., Shore, J. E., Bergna, M. A., Golod, D., Elenko, E., et al. (2026) · American Journal of Respiratory and Critical Care Medicine · doi:10.1093/ajrccm/aamag155 · Cited by 4 · see citing works
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3D alveolar organoid drug screening model for targeting TGF-β1 in pulmonary fibrosis
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Stimuli-specific senescence of primary human lung fibroblasts modulates alveolar stem cell functionPreprint
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Modeling Molecular Mechanisms of Pirfenidone Interaction with KinasesPreprint
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Biodegradable Nanoparticle-in-Implant Platform for Sustained and Light-Boosted Pirfenidone DeliveryPreprint
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- Authors
- Ballester, B., Milara, J., & Cortijo, J.
- Affiliations
- Universitat de València (ES)
- Corresponding author
- Ballester, Beatriz
- Milara, Javier
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2020-04-14
- Volume
- 11
- Issue
- 15
- Pages
- 1306-1320
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC7170494
- OpenAlex
- W3016790907
- Cited by
- 43
- References
- 59
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 6 · 2020: 3
- FWCI
- 3.10
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- American Concrete Institute Foundation
- Generalitat Valenciana (ACIF/2016/341, 2017/023/UV, ACIF/2016, Prometeo 2017/023/UV)
- European Regional Development Fund (SAF2017-82913-R, SAF2017)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Keywords
- pirfenidone, idiopathic pulmonary fibrosis, MUC1, TGF-β1 signaling, Smad3, β-catenin, Smad binding element, lung fibroblasts, alveolar epithelial cells, antifibrotic mechanism, Smad3 nuclear translocation, Smad3 phosphorylation
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