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Article Open Access

FGF4 alleviates the lung cell damage caused by high glucose via AMPK‑PGC‑1 signaling axis in vitro and in vivo

  • Authors:
    • Qiujuan Fu
    • Yongfang Ou
    • Qin Wu
    • Jue Gong
    • Feixia Li
    • Tuxing Wang
    • Zhitai Lin
    • Kejie Huang
    • Jianlong Xie
  • View Affiliations / Copyright

    Affiliations: Pathological Diagnosis Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China, Department of Thoracic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
    Copyright: © Fu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 39
    |
    Published online on: December 5, 2025
       https://doi.org/10.3892/ijmm.2025.5710
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Abstract

Long‑term hyperglycemia can damage the capillaries and neural regulation of the lungs, leading to pulmonary microvascular disease and neural regulation disorders, causing abnormalities in lung structure and function. The present study explored the effect of fibroblast growth factor (FGF)4 as a potential therapeutic growth factor on the effect of hyperglycemia on the lungs in vitro and in vivo models. The effect of FGF4 on the damage of lung cells caused by high glucose was evaluated in vitro and in vivo by a series of biochemical experiments (indirect immunofluorescence, western blotting, immunohistochemistry and siRNA). The results showed that FGF4 could effectively alleviate the inhibition of lung cell proliferation caused by high glucose. Further experiments found that high glucose caused inflammation, oxidative stress and fibrosis of lung cells, while the above pathological reactions were alleviated after treatment with FGF4. Further mechanism research showed that FGF4 treatment could markedly improve the survival rate of lung cells, reduce cell death and inflammatory responses and enhance the antioxidant stress resistance of cells. These effects are achieved by activating the adenosine monophosphate (AMP)‑activated protein kinase (AMPK)‑peroxisome proliferator‑activated receptor coactivator 1 (PGC‑1) signaling axis, which plays an important role in regulating cellular metabolism, antioxidant stress and anti‑inflammatory responses. In vivo experiments further confirmed the mitigating effect of FGF4 on lung tissue damage caused by high glucose. FGF4 treatment to diabetic model animals, lung function can be markedly improved and the degree of lung inflammation and fibrosis can be reduced. In summary, FGF4 exhibits a significant mitigating effect on high‑glucose‑induced lung cell damage through the AMPK‑PGC‑1 signaling axis, providing a new strategy for the treatment of diabetes and its pulmonary complications.
View Figures

Figure 1

FGF4 alleviated the damage of lung
cells caused by hyperglycemia. (A) Cell proliferation is promoted
by FGF4 treatment. (B) The effect of FGF4 on the expression of
cyclinD1 and PCNA in cells. (C) The effect of FGF4 on the
expression of p21 and p53. *P<0.05,
**P<0.01, ***P<0.001. FGF4, fibroblast
growth factor 4; PCNA, proliferating cell nuclear antigen.

Figure 2

The effect of FGF4 on high
glucose-induced inflammation and oxidative stress in lung cells.
(A) The effect of FGF4 on IL-6 and IL-1β by western-blot analysis.
(B) The effect of FGF4 on the expression levels of p-IκB, p-P65 and
p-STAT3. *P<0.05, **P<0.01,
***P<0.001. FGF4, fibroblast growth factor 4; p-,
phosphorylated.

Figure 3

The effect of FGF4 on high
glucose-induced lung fibrosis. (A) The effect of FGF4 on the
expression of FN1, α-SMA, E-cadherin and N-cadherin. (B) Indirect
immunofluorescence analysis of the effect of FGF4 on fibrosis.
Scale bar, 50 μm. *P<0.05,
**P<0.01, ***P<0.001. FGF4, fibroblast
growth factor 4; FN1, fibronectin 1; α-SMA, α-smooth muscle
actin.

Figure 4

FGF4 alleviates the inhibition of
mitochondrial autophagy caused by high glucose. (A) Evaluation of
the level of autophagy in the presence of high glucose. (B) High
glucose inhibited the autophagy. (C) FGF4 promoted the autophagy
through using specific fluorescent probe. (D) Co-localization also
showed that autophagy of mitochondria was partially restored under
treatment with FGF4. *P<0.05, **P<0.01,
***P<0.001. FGF4, fibroblast growth factor 4; PINK1,
PTEN-induced kinase 1.

Figure 5

The effect of FGF4 on the cGAS-STING
signaling pathway triggered by high glucose. (A) FGF4 inhibited
high glucose-promoted the release of mitochondrial DNA into the
cytoplasm. Scale bar, 50 μM. (B) FGF4 restored the
expression of PGC-1 and TFAM. (C) FGF4 inhibited cGAS-STING
signaling. (D) The effect of FGF4 was blocked when AMPK was
inhibited. *P<0.05, **P<0.01,
***P<0.001. FGF4, fibroblast growth factor 4; PGC-1,
activated receptor coactivator 1; TFAM, mitochondrial transcription
factor A; AMPK, adenosine monophosphate activated protein
kinase.

Figure 6

The effect of FGF4 on the body weight
and blood glucose of mice. (A) Effect of FGF4 on the body weight of
mice. (B) The effect of FGF4 on blood glucose. FGF4, fibroblast
growth factor 4; DM, diabetes mellitus.

Figure 7

Effect of FGF4 on lung tissue
inflammation in diabetic mice. (A) H&E staining analysis of the
effect of FGF4 on the lung tissue of diabetic mice. (B)
Immunohistochemical analysis of the effect of FGF4 on lung
inflammation. Scale bar, 60 μm. (C) FGF4 treatment
alleviated the infiltration of inflammatory cells. (D) The effect
of FGF4 on the expression of NF-κB. *P<0.05,
**P<0.01, ***P<0.001. FGF4, fibroblast
growth factor 4; H&E, hematoxylin and eosin; DM, diabetes
mellitus.

Figure 8

The effect of FGF4 on pulmonary
fibrosis in diabetic mice. (A) Masson staining analysis of the
effect of FGF4 on lung fibrosis. (B) The effect of FGF4 on marker
molecules for lung tissue fibrosis. FGF4, fibroblast growth factor
4; DM, diabetes mellitus. Scale bar, 200 μM.
*P<0.05, **P<0.01,
***P<0.001.

Figure 9

Effect of FGF4 on oxidative stress in
lung tissue of diabetic mice. (A) The effect of FGF4 on ROS by DHE.
(B) The effect of FGF4 on 4-HNE/8-OHdG (scale bar, 60 μm).
(C) The effect of FGF4 on the expression of SOD1 and CAT.
***P<0.001. FGF4, fibroblast growth factor 4; ROS,
reactive oxygen species; SOD, superoxide dismutase; CAT, catalase;
DM, diabetes mellitus.

Figure 10

FGF4 improves mitochondrial autophagy
and the cGAS-STING signaling pathway. (A) FGF4 alleviated the
mitochondrial autophagy by western blotting. (B) FGF4 weakened the
cGAS-STING signaling pathway. (C) FGF4 enhanced the expression of
PGC-1-TFAM. (D) FGF4 treatment increased AMPK phosphorylation in
vivo. *P<0.05, **P<0.01,
***P<0.001. FGF4, fibroblast growth factor 4; PGC-1,
activated receptor coactivator 1; TFAM, mitochondrial transcription
factor A; AMPK, adenosine monophosphate activated protein
kinase.
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Copy and paste a formatted citation
Spandidos Publications style
Fu Q, Ou Y, Wu Q, Gong J, Li F, Wang T, Lin Z, Huang K and Xie J: FGF4 alleviates the lung cell damage caused by high glucose via AMPK‑PGC‑1 signaling axis <em>in vitro</em> and <em>in vivo</em>. Int J Mol Med 57: 39, 2026.
APA
Fu, Q., Ou, Y., Wu, Q., Gong, J., Li, F., Wang, T. ... Xie, J. (2026). FGF4 alleviates the lung cell damage caused by high glucose via AMPK‑PGC‑1 signaling axis <em>in vitro</em> and <em>in vivo</em>. International Journal of Molecular Medicine, 57, 39. https://doi.org/10.3892/ijmm.2025.5710
MLA
Fu, Q., Ou, Y., Wu, Q., Gong, J., Li, F., Wang, T., Lin, Z., Huang, K., Xie, J."FGF4 alleviates the lung cell damage caused by high glucose via AMPK‑PGC‑1 signaling axis <em>in vitro</em> and <em>in vivo</em>". International Journal of Molecular Medicine 57.2 (2026): 39.
Chicago
Fu, Q., Ou, Y., Wu, Q., Gong, J., Li, F., Wang, T., Lin, Z., Huang, K., Xie, J."FGF4 alleviates the lung cell damage caused by high glucose via AMPK‑PGC‑1 signaling axis <em>in vitro</em> and <em>in vivo</em>". International Journal of Molecular Medicine 57, no. 2 (2026): 39. https://doi.org/10.3892/ijmm.2025.5710
Copy and paste a formatted citation
x
Spandidos Publications style
Fu Q, Ou Y, Wu Q, Gong J, Li F, Wang T, Lin Z, Huang K and Xie J: FGF4 alleviates the lung cell damage caused by high glucose via AMPK‑PGC‑1 signaling axis <em>in vitro</em> and <em>in vivo</em>. Int J Mol Med 57: 39, 2026.
APA
Fu, Q., Ou, Y., Wu, Q., Gong, J., Li, F., Wang, T. ... Xie, J. (2026). FGF4 alleviates the lung cell damage caused by high glucose via AMPK‑PGC‑1 signaling axis <em>in vitro</em> and <em>in vivo</em>. International Journal of Molecular Medicine, 57, 39. https://doi.org/10.3892/ijmm.2025.5710
MLA
Fu, Q., Ou, Y., Wu, Q., Gong, J., Li, F., Wang, T., Lin, Z., Huang, K., Xie, J."FGF4 alleviates the lung cell damage caused by high glucose via AMPK‑PGC‑1 signaling axis <em>in vitro</em> and <em>in vivo</em>". International Journal of Molecular Medicine 57.2 (2026): 39.
Chicago
Fu, Q., Ou, Y., Wu, Q., Gong, J., Li, F., Wang, T., Lin, Z., Huang, K., Xie, J."FGF4 alleviates the lung cell damage caused by high glucose via AMPK‑PGC‑1 signaling axis <em>in vitro</em> and <em>in vivo</em>". International Journal of Molecular Medicine 57, no. 2 (2026): 39. https://doi.org/10.3892/ijmm.2025.5710
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