Cited by 43Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisTGF-β signaling in diseasesPulmonary Hypertension Research and Treatments

Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation

Open access
Ballester, Beatriz, Milara, Javier, Cortijo, Julio·2020·Oncotarget

Abstract

// 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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.18632/oncotarget.27526

Cites

59 of 59 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Ballester, B., Milara, J., & Cortijo, J.
Affiliations
Universitat de València (ES)
Corresponding author
  • Ballester, Beatriz
  • Milara, Javier
Venue
Oncotarget
Published
2020-04-14
Volume
11
Issue
15
Pages
1306-1320
ISSN
1949-2553 (ISSN-L)
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review