NDLI: Inositol possesses antifibrotic activity and mitigates pulmonary fibrosis

Content Provider	Springer Nature : BioMed Central
Author	Li, Ji-Min Chang, Wen-Hsin Li, Linhui Yang, David C. Hsu, Ssu-Wei Kenyon, Nicholas J. Chen, Ching-Hsien
Abstract	Background Myo-inositol (or inositol) and its derivatives not only function as important metabolites for multiple cellular processes but also act as co-factors and second messengers in signaling pathways. Although inositol supplementation has been widely studied in various clinical trials, little is known about its effect on idiopathic pulmonary fibrosis (IPF). Recent studies have demonstrated that IPF lung fibroblasts display arginine dependency due to loss of argininosuccinate synthase 1 (ASS1). However, the metabolic mechanisms underlying ASS1 deficiency and its functional consequence in fibrogenic processes are yet to be elucidated. Methods Metabolites extracted from primary lung fibroblasts with different ASS1 status were subjected to untargeted metabolomics analysis. An association of ASS1 deficiency with inositol and its signaling in lung fibroblasts was assessed using molecular biology assays. The therapeutic potential of inositol supplementation in fibroblast phenotypes and lung fibrosis was evaluated in cell-based studies and a bleomycin animal model, respectively. Results Our metabolomics studies showed that ASS1-deficient lung fibroblasts derived from IPF patients had significantly altered inositol phosphate metabolism. We observed that decreased inositol-4-monophosphate abundance and increased inositol abundance were associated with ASS1 expression in fibroblasts. Furthermore, genetic knockdown of ASS1 expression in primary normal lung fibroblasts led to the activation of inositol-mediated signalosomes, including EGFR and PKC signaling. Treatment with inositol significantly downregulated ASS1 deficiency-mediated signaling pathways and reduced cell invasiveness in IPF lung fibroblasts. Notably, inositol supplementation also mitigated bleomycin-induced fibrotic lesions and collagen deposition in mice. Conclusion These findings taken together demonstrate a novel function of inositol in fibrometabolism and pulmonary fibrosis. Our study provides new evidence for the antifibrotic activity of this metabolite and suggests that inositol supplementation may be a promising therapeutic strategy for IPF.
Related Links	https://respiratory-research.biomedcentral.com/counter/pdf/10.1186/s12931-023-02421-6.pdf
Ending Page	15
Page Count	15
Starting Page	1
File Format	HTM / HTML
DOI	10.1186/s12931-023-02421-6
Journal	Respiratory Research
Issue Number	1
Volume Number	24
Language	English
Publisher	BioMed Central
Publisher Date	2023-05-16
Access Restriction	Open
Subject Keyword	Pneumology Respiratory System IPF Lung fibroblasts Fibrometabolism Myo-inositol ASS1 Pneumology/Respiratory System
Content Type	Text
Resource Type	Article
Subject	Pulmonary and Respiratory Medicine
Journal Impact Factor	4.7/2023
5-Year Journal Impact Factor	5.3/2023

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