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Effects of the WNT signaling pathway on inflammation and fibrosis in idiopathic pulmonary fibrosis: Clinical, radiological and molecular evaluation

  • Authors:
    • İlknur Kaya
    • Ayşe Koçak Sezgi̇n
    • Meliha Koldemi̇r Gündüz
    • Şebnem Emine Parspur
    • Feride Marim
    • Mehmet Doğan
    • Ümran Toru Erbay
  • View Affiliations / Copyright

    Affiliations: Department of Chest Diseases, Faculty of Medicine, Kütahya Health Sciences University, Kütahya 43100, Türkiye, Department of Medical Biochemistry, Faculty of Medicine, Kütahya Health Sciences University, Kütahya 43100, Türkiye, Department of Engineering Basic Sciences, Faculty of Engineering and Natural Sciences, Kütahya Health Sciences University, Kütahya 43100, Türkiye
    Copyright: © Kaya et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 106
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    Published online on: February 11, 2026
       https://doi.org/10.3892/etm.2026.13101
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by irreversible fibrosis, radiological honeycombing and a progressive decline in pulmonary function. Although antifibrotic agents such as pirfenidone and nintedanib can slow disease progression, these agents fail to reverse established structural damage, underscoring the urgent need for novel therapeutic strategies. Notably, the WNT signaling pathway has been implicated in fibrogenesis, suggesting it may represent a promising therapeutic target in IPF. The present study aimed to elucidate the role of WNT signaling in IPF pathogenesis, and to evaluate the antifibrotic and anti‑inflammatory effects of the WNT inhibitors ETC‑159 and LGK‑974 in vitro. A prospective case‑control study was conducted, including 33 patients with IPF and 23 healthy controls. WNT gene expression in peripheral blood was quantified using quantitative PCR. Fibrotic markers [α‑smooth muscle actin (α‑SMA) and collagen type I] and inflammatory cytokines (IL‑1β, IL‑6 and TGF‑β2) were measured by ELISA. Additionally, LL29 (AnHa) fibroblasts from a patient with IPF were treated with ETC‑159 or LGK‑974 to assess molecular and phenotypic responses. Patients with IPF exhibited significant upregulation of WNT‑2, WNT‑4, WNT‑6, WNT‑7a/b and WNT‑10a/b, whereas WNT‑1 and WNT‑3a showed no significant change. Collagen type I and α‑SMA levels were also markedly elevated in IPF. Treatment with LGK‑974 significantly reduced both α‑SMA and collagen type I expression, whereas ETC‑159 selectively decreased collagen type I. Both inhibitors suppressed IL‑6, whereas LGK‑974 additionally reduced IL‑1β. In conclusion, aberrant activation of WNT signaling may contribute to fibrogenesis and inflammation in IPF. Pharmacological inhibition of this pathway, particularly with LGK‑974, exerts potent antifibrotic and anti‑inflammatory effects, highlighting WNT signaling as a viable therapeutic target for IPF.
View Figures

Figure 1

Comparison of the fibrotic markers (A)
collagen type I and (B) α-SMA in the IPF group and control group
*P<0.05, **P<0.01 vs. control. α-SMA,
α-smooth muscle actin; IPF, idiopathic pulmonary hypertension.

Figure 2

Comparison of the fibrotic markers (A)
α-SMA and (B) collagen type I after WNT inhibitor ETC-159 and
LGK-974 treatments in IPF cells at the gene level.
*P<0.05 vs. control. α-SMA, α-smooth muscle
actin.

Figure 3

Comparison of (A) TGF-b2, (B) IL-6
and (C) IL-1b levels after WNT inhibitor ETC-159 and LGK-974
treatments in IPF cells at the mRNA level. *P<0.05,
**P<0.01 vs. control. IPF, idiopathic pulmonary
hypertension.
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Copy and paste a formatted citation
Spandidos Publications style
Kaya I, Sezgi̇n AK, Gündüz MK, Parspur ŞE, Marim F, Doğan M and Erbay ÜT: Effects of the WNT signaling pathway on inflammation and fibrosis in idiopathic pulmonary fibrosis: Clinical, radiological and molecular evaluation. Exp Ther Med 31: 106, 2026.
APA
Kaya, I., Sezgi̇n, A.K., Gündüz, M.K., Parspur, Ş.E., Marim, F., Doğan, M., & Erbay, Ü.T. (2026). Effects of the WNT signaling pathway on inflammation and fibrosis in idiopathic pulmonary fibrosis: Clinical, radiological and molecular evaluation. Experimental and Therapeutic Medicine, 31, 106. https://doi.org/10.3892/etm.2026.13101
MLA
Kaya, I., Sezgi̇n, A. K., Gündüz, M. K., Parspur, Ş. E., Marim, F., Doğan, M., Erbay, Ü. T."Effects of the WNT signaling pathway on inflammation and fibrosis in idiopathic pulmonary fibrosis: Clinical, radiological and molecular evaluation". Experimental and Therapeutic Medicine 31.4 (2026): 106.
Chicago
Kaya, I., Sezgi̇n, A. K., Gündüz, M. K., Parspur, Ş. E., Marim, F., Doğan, M., Erbay, Ü. T."Effects of the WNT signaling pathway on inflammation and fibrosis in idiopathic pulmonary fibrosis: Clinical, radiological and molecular evaluation". Experimental and Therapeutic Medicine 31, no. 4 (2026): 106. https://doi.org/10.3892/etm.2026.13101
Copy and paste a formatted citation
x
Spandidos Publications style
Kaya I, Sezgi̇n AK, Gündüz MK, Parspur ŞE, Marim F, Doğan M and Erbay ÜT: Effects of the WNT signaling pathway on inflammation and fibrosis in idiopathic pulmonary fibrosis: Clinical, radiological and molecular evaluation. Exp Ther Med 31: 106, 2026.
APA
Kaya, I., Sezgi̇n, A.K., Gündüz, M.K., Parspur, Ş.E., Marim, F., Doğan, M., & Erbay, Ü.T. (2026). Effects of the WNT signaling pathway on inflammation and fibrosis in idiopathic pulmonary fibrosis: Clinical, radiological and molecular evaluation. Experimental and Therapeutic Medicine, 31, 106. https://doi.org/10.3892/etm.2026.13101
MLA
Kaya, I., Sezgi̇n, A. K., Gündüz, M. K., Parspur, Ş. E., Marim, F., Doğan, M., Erbay, Ü. T."Effects of the WNT signaling pathway on inflammation and fibrosis in idiopathic pulmonary fibrosis: Clinical, radiological and molecular evaluation". Experimental and Therapeutic Medicine 31.4 (2026): 106.
Chicago
Kaya, I., Sezgi̇n, A. K., Gündüz, M. K., Parspur, Ş. E., Marim, F., Doğan, M., Erbay, Ü. T."Effects of the WNT signaling pathway on inflammation and fibrosis in idiopathic pulmonary fibrosis: Clinical, radiological and molecular evaluation". Experimental and Therapeutic Medicine 31, no. 4 (2026): 106. https://doi.org/10.3892/etm.2026.13101
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