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Targeting alveolar type II cell dysfunction in idiopathic pulmonary fibrosis: Molecular mechanisms and emerging therapeutic strategies (Review)

  • Authors:
    • Tianhao Xie
    • Kang Hu
    • Shu Pan
    • Xin Tong
    • Haitong Huang
    • Hao Ding
    • Jun Zhao
  • View Affiliations / Copyright

    Affiliations: Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
    Copyright: © Xie et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 256
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    Published online on: July 13, 2026
       https://doi.org/10.3892/ijmm.2026.5927
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal and progressive form of interstitial lung pathology. It is characterized by the relentless replacement of functional alveolar epithelium by aberrant fibroblasts and excessive extracellular matrix deposition, resulting in respiratory failure. Currently, the treatment options for this disease are limited. Approved antifibrotic agents primarily slow disease progression by inhibiting fibroblast proliferation and downstream fibrotic pathways; however, they do not halt or reverse the underlying pathology. Recent studies have elucidated the proliferation and differentiation characteristics of type II alveolar epithelial (AT2) cells, identifying them as facultative stem cells of the distal lung with significant therapeutic potential in IPF. However, there are certain limitations in clinical translation. This review comprehensively summarizes the regulatory pathways governing AT2 proliferation and differentiation, and investigates key pathogenic drivers of IPF, including cellular senescence and mechanical tension. Furthermore, it evaluates current treatment strategies and methods to facilitate safer, more effective clinical delay or even reversal of pulmonary fibrosis by identifying or improving existing therapies.
View Figures

Figure 1

Signaling regulatory pathways of type
II alveolar epithelial cells. Akt, protein kinase B; APC,
adenomatous polyposis coli; α-SMA, α-smooth muscle actin; BMP, bone
morphogenetic protein; CBP, CREB-binding protein; Dlk1, delta-like
non-canonical Notch ligand 1; FGF-2, fibroblast growth factor 2;
GREM1, gremlin 1; GSK-3, glycogen synthase kinase 3; HES1, hairy
and enhancer of split-1; HOPX, HOP homeobox; LAMP3, lysosomal
associated membrane protein 3; MAML, mastermind-like protein;
MMP-7, matrix metalloproteinase-7; mTOR, mammalian target of
rapamycin; NICD, Notch intracellular domain; P, phosphate; PDGFRα,
platelet-derived growth factor receptor α; PIK3, phosphoinositide
3-kinase; PTEN, phosphatase and tensin homolog; RBPJ, recombination
signal binding protein for immunoglobulin kappa J region; SMAD,
small mothers against decapentaplegic; SP, surfactant protein;
TCF/LEF, T-cell factor/lymphoid enhancer-binding factor; TF,
transcription factor; TGF-β1, transforming growth factor β1; Wnt,
wingless-related integration site.

Figure 2

EMT-regulatory miRNA-TF networks.
Akt, protein kinase B; α-SMA, α-smooth muscle actin; cdh-1,
cadherin-1; E-cadherin, epithelial cadherin; EMT,
epithelial-mesenchymal transition; ERα, estrogen receptor α; ESR1,
estrogen receptor 1; Gli1/2, glioma-associated oncogene homolog
1/2; GSK3β, glycogen synthase kinase 3β; HIF-1α, hypoxia-inducible
factor 1α; IL-6, interleukin 6; LRP, lipoprotein receptor-related
protein; MAPK, mitogen-activated protein kinase; miRNA-200, micro
ribonucleic acid-200; N-cadherin, neural cadherin; NF-κB, nuclear
factor Kb; NuRD, nucleosome remodeling and deacetylase; p53, tumor
protein 53; PRC, polycomb repressive complex; RKIP, Raf kinase
inhibitor protein; SHH, sonic hedgehog; SMAD, small mothers against
decapentaplegic; SMO, smoothened; SNAIL1, snail family
transcriptional repressor 1; STAT3, signal transducer and activator
of transcription 3; TGF-β, transforming growth factor beta; TWIST1,
Twist family bhlh transcription factor 1; Wnt, wingless-related
integration site; ZEB1/2, zinc finger E-box binding homeobox 1/2;
ZNF281, zinc finger protein 281.
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Copy and paste a formatted citation
Spandidos Publications style
Xie T, Hu K, Pan S, Tong X, Huang H, Ding H and Zhao J: Targeting alveolar type II cell dysfunction in idiopathic pulmonary fibrosis: Molecular mechanisms and emerging therapeutic strategies (Review). Int J Mol Med 58: 256, 2026.
APA
Xie, T., Hu, K., Pan, S., Tong, X., Huang, H., Ding, H., & Zhao, J. (2026). Targeting alveolar type II cell dysfunction in idiopathic pulmonary fibrosis: Molecular mechanisms and emerging therapeutic strategies (Review). International Journal of Molecular Medicine, 58, 256. https://doi.org/10.3892/ijmm.2026.5927
MLA
Xie, T., Hu, K., Pan, S., Tong, X., Huang, H., Ding, H., Zhao, J."Targeting alveolar type II cell dysfunction in idiopathic pulmonary fibrosis: Molecular mechanisms and emerging therapeutic strategies (Review)". International Journal of Molecular Medicine 58.3 (2026): 256.
Chicago
Xie, T., Hu, K., Pan, S., Tong, X., Huang, H., Ding, H., Zhao, J."Targeting alveolar type II cell dysfunction in idiopathic pulmonary fibrosis: Molecular mechanisms and emerging therapeutic strategies (Review)". International Journal of Molecular Medicine 58, no. 3 (2026): 256. https://doi.org/10.3892/ijmm.2026.5927
Copy and paste a formatted citation
x
Spandidos Publications style
Xie T, Hu K, Pan S, Tong X, Huang H, Ding H and Zhao J: Targeting alveolar type II cell dysfunction in idiopathic pulmonary fibrosis: Molecular mechanisms and emerging therapeutic strategies (Review). Int J Mol Med 58: 256, 2026.
APA
Xie, T., Hu, K., Pan, S., Tong, X., Huang, H., Ding, H., & Zhao, J. (2026). Targeting alveolar type II cell dysfunction in idiopathic pulmonary fibrosis: Molecular mechanisms and emerging therapeutic strategies (Review). International Journal of Molecular Medicine, 58, 256. https://doi.org/10.3892/ijmm.2026.5927
MLA
Xie, T., Hu, K., Pan, S., Tong, X., Huang, H., Ding, H., Zhao, J."Targeting alveolar type II cell dysfunction in idiopathic pulmonary fibrosis: Molecular mechanisms and emerging therapeutic strategies (Review)". International Journal of Molecular Medicine 58.3 (2026): 256.
Chicago
Xie, T., Hu, K., Pan, S., Tong, X., Huang, H., Ding, H., Zhao, J."Targeting alveolar type II cell dysfunction in idiopathic pulmonary fibrosis: Molecular mechanisms and emerging therapeutic strategies (Review)". International Journal of Molecular Medicine 58, no. 3 (2026): 256. https://doi.org/10.3892/ijmm.2026.5927
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