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Review
. 2025 Jun 25:13:1608750.
doi: 10.3389/fcell.2025.1608750. eCollection 2025.

Targeting alveolar epithelial cell metabolism in pulmonary fibrosis: Pioneering an emerging therapeutic strategy

Tengkun Dai  1   2 , Yidan Liang  1   2 , Xin Li  1   2 , Jiamin Zhao  1   2 , Guangqin Li  2 , Qihong Li  2 , Lin Xu  1   2 , Juanjuan Zhao  1   2
Affiliations
Review

Targeting alveolar epithelial cell metabolism in pulmonary fibrosis: Pioneering an emerging therapeutic strategy

Tengkun Dai et al. Front Cell Dev Biol. .

Abstract

Pulmonary fibrosis (PF) is a chronic and progressive lung disease, characterized by excessive deposition of fibrotic connective tissue within the lungs. Advances in transcriptomics, proteomics, and metabolomics have enhanced our understanding of PF's pathogenesis. Recent studies have indicates that metabolic abnormalities in alveolar epithelial cells (AECs) play a central role in the pathogenesis of PF. Metabolic reprogramming of AECs affects cellular senescence, endoplasmic reticulum stress, and oxidative stress in AECs, while also promoting fibrotic progression through various signaling pathways. This review focuses on therapeutic strategies targeting the metabolism of AECs. It comprehensively explores the role of metabolic pathways through glucose metabolism, lipid metabolism, and amino acid metabolism in the pathogenesis of PF, aiming to provide novel theoretical support and research perspectives for preventing and treating pulmonary fibrosis.

Keywords: alveolar epithelial cells; amino acid metabolism; energy metabolism; glucose metabolism; lipid metabolism; metabolic reprogramming; pathogenesis; pulmonary fibrosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
An overview of key events in the progress of research on metabolic alterations in AECs in pulmonary fibrosis.
FIGURE 2
FIGURE 2
Disturbed lipid metabolism in AECs in PF. When AEC2 is damaged by smoke, viruses, etc., fatty acid biosynthesis, fatty acid β-oxidation, and other lipid-related components are downregulated, leading to fibroblast activation tissue remodeling, which in turn leads to pulmonary fibrosis.
FIGURE 3
FIGURE 3
The molecular mechanism of AEC2 lipid metabolism in PF. Specifically speaking, Elovl6 deficiency led to changes in the composition of fatty acid content in AEC2 cells, including an increase in C16 PA and a decrease in C18 OA and C18 LA, which triggered a disturbance in lipid metabolism; this metabolic dysregulation further contributed to the progression of pulmonary fibrosis by inducing apoptosis, ROS production, TGF-β1 and other pathways.
FIGURE 4
FIGURE 4
The molecular mechanism of AEC2 carbohydrate metabolism in PF. For example, AEC2 cells in patients with PF, on the other hand, tend to undergo inefficient oxidative metabolism, produce more glycolytic lactic acid, and increase TGF-β expression, thereby promoting fibrogenesis.
FIGURE 5
FIGURE 5
The molecular mechanism of AEC2 metabolism in PF.
FIGURE 6
FIGURE 6
The molecular mechanism of AEC2 glutamine metabolism in PF. Decrease in glutamine and glutamate in damaged AEC2 leads to decrease in α-KG and AKT hindering cell proliferation and differentiation, on the contrary increase in exogenous glutamine restores normal TCA cycling in mitochondria and promotes cell proliferation and differentiation.
FIGURE 7
FIGURE 7
A diagram of several key scientific issues that remain to be addressed in the future.
See this image and copyright information in PMC

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References

    1. Abedini F., Ismail M., Hosseinkhani H., Ibrahim T. A., Omar A. R., Chong P. P., et al. (2011). Effects of CXCR4 siRNA/dextran-spermine nanoparticles on CXCR4 expression and serum LDH levels in a mouse model of colorectal cancer metastasis to the liver. Cancer Manag. Res. 3, 301–309. 10.2147/CMR.S11678 - DOI - PMC - PubMed
    1. Acharya R., Chakraborty M., Chakraborty J. (2019). Prospective treatment of Parkinson's disease by a siRNA-LDH nanoconjugate. Medchemcomm 10 (2), 227–233. 10.1039/c8md00501j - DOI - PMC - PubMed
    1. Alsafadi H. N., Staab-Weijnitz C. A., Lehmann M., Lindner M., Peschel B., Königshoff M., et al. (2017). An ex vivo model to induce early fibrosis-like changes in human precision-cut lung slices. Am. J. Physiol. - Lung Cell Mol. Physiol. 312, L896-L902–L902. 10.1152/ajplung.00084.2017 - DOI - PubMed
    1. Álvarez D., Cárdenes N., Sellarés J., Bueno M., Corey C., Hanumanthu V. S., et al. (2017). IPF lung fibroblasts have a senescent phenotype. Am. J. Physiol. Lung Cell Mol. Physiol. 313 (6), L1164–L1173. 10.1152/ajplung.00220.2017 - DOI - PMC - PubMed
    1. Araya J., Kojima J., Takasaka N., Ito S., Fujii S., Hara H., et al. (2013). Insufficient autophagy in idiopathic pulmonary fibrosis. Am. J. Physiol. Lung Cell Mol. Physiol. 304 (1), L56–L69. 10.1152/ajplung.00213.2012 - DOI - PubMed

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