Evidence that metformin promotes fibrosis resolution via activating alveolar epithelial stem cells and FGFR2b signaling.
10.1016/j.apsb.2025.07.023
- Author:
Yuqing LV
1
;
Yanxia ZHANG
2
;
Xueli GUO
2
;
Baiqi HE
2
;
Haibo XU
2
;
Ming XU
2
;
Lihui ZOU
3
;
Handeng LYU
2
;
Jin WU
2
;
Pingping ZENG
3
;
Saverio BELLUSCI
1
;
Xuru JIN
1
;
Chengshui CHEN
1
;
Young-Chang CHO
4
;
Xiaokun LI
3
;
Jin-San ZHANG
1
Author Information
1. The Quzhou Affiliated Hospital of Wenzhou Medical University (Quzhou People's Hospital), Quzhou 324000, China.
2. Medical Research Center, Zhejiang Key Laboratory of Interventional Pulmonology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.
3. International Collaborative Center on Growth Factor Research, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
4. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju 61186, Republic of Korea.
- Publication Type:Journal Article
- Keywords:
AMPK;
Alveolar stem cell;
FGFR2b;
Injury-activated alveolar progenitor;
Metformin;
Pulmonary fibrosis;
Transgenic mice
- From:
Acta Pharmaceutica Sinica B
2025;15(9):4711-4729
- CountryChina
- Language:English
-
Abstract:
Idiopathic pulmonary fibrosis (IPF) is a progressive disease lacking effective therapy. Metformin, an antidiabetic medication, has shown promising therapeutic properties in preclinical fibrosis models; however, its precise cellular targets and associated mechanisms in fibrosis resolution remain incompletely defined. Most research on metformin's effects has focused on mesenchymal and inflammatory responses with limited attention to epithelial cells. In this study, we utilized Sftpc lineage-traced and Fgfr2b conditional knockout mice, along with BMP2/PPARγ and AMPK inhibitors, to explore metformin's impact on alveolar epithelial cells in a bleomycin-induced pulmonary fibrosis model and cell culture. We found that metformin increased the proliferation and differentiation of alveolar type 2 (AT2) cells, particularly the recently identified injury-activated alveolar progenitors (IAAPs)-a subpopulation characterized by low SFTPC expression but enriched for PD-L1. Single-cell RNA sequencing revealed a reduction in apoptosis among mature AT2 cells. Interestingly, metformin's therapeutic effects were not significantly affected by BMP2 or PPARγ inhibition, which blocked the lipogenic differentiation of myofibroblasts. However, Fgfr2b deletion in Sftpc lineage cells significantly impaired metformin's ability to promote fibrosis resolution, a process linked to AMPK signaling. In conclusion, metformin alleviates fibrosis by directly activating AT2 cells, especially the IAAPs, through a mechanism that involves AMPK and FGFR2b signaling, but is largely independent of BMP2/PPARγ pathways.
