The crucial function of IDO1 in pulmonary fibrosis: From the perspective of mitochondrial fusion in lung fibroblasts and targeted molecular inhibition.
10.1016/j.apsb.2025.04.027
- Author:
Lei WANG
1
;
Shanchun GE
1
;
Ye ZHANG
1
;
Deqin FENG
2
;
Ting ZHU
3
;
Louqian ZHANG
4
;
Chaofeng ZHANG
1
Author Information
1. Sino-Jan Joint Lab of Natural Health Products Research, School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing 210009, China.
2. State Key Laboratory of Microbial Resources Chinese Academy of Sciences, Beijing 100049, China.
3. Institute of Neuroregeneration & Neurorehabilitation, Department of Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao 266021, China.
4. Department of Thoracic Surgery, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210031, China.
- Publication Type:Journal Article
- Keywords:
Indoleamine 2,3-dioxygenase 1;
Lipid metabolism;
Lung fibroblasts;
Mitochondrial dynamics;
Pulmonary fibrosis;
Targets;
Transcriptomics;
Wedelolactone
- From:
Acta Pharmaceutica Sinica B
2025;15(6):3125-3148
- CountryChina
- Language:English
-
Abstract:
The pathogenesis of pulmonary fibrosis (PF) is complex. It is characterized by myofibroblast hyperplasia and deposition of collagen protein. Indoleamine 2,3-dioxygenase 1 (IDO1) is expressed in lung fibroblasts and epithelial cells, but its functions in lung homeostasis and diseases remain elusive. Here, we characterize the critical role of IDO1 in PF patients and bleomycin (BLM)-induced PF mouse models. We find that IDO1 is significantly upregulated in the fibrotic lungs of patients and mice, showing a positive correlation with genes characteristic of fibrosis. Functionally, IDO1 knockout inhibits lung fibroblast proliferation, differentiation, mitochondrial biogenesis, and mitochondrial oxidative phosphorylation. Conversely, IDO1 overexpression and accumulation of kynurenine (Kyn) exacerbate progressive lung fibrosis. Mechanistically, IDO1-deletion activated profound mitochondrial fusion-enhanced potentially the capacity for fatty acid oxidation, along with activation of de novo glycolytic serine/glycine synthesis pathways and mitochondrial one-carbon metabolism. Wedelolactone (WEL), a small molecule IKK inhibitor, is found to strongly bind to IDO1 and effectively protect mice from PF in an IDO1-dependent manner. Collectively, this study characterizes a promotor role for IDO1 in PF and suggests a potential avenue of targeting IDO1 to treat lung diseases.
