Therapeutic targeting of argininosuccinate synthase 1 (ASS1)-deficient pulmonary fibrosis.

Abstract

Argininosuccinate synthase 1 (ASS1) serves as a critical enzyme in arginine biosynthesis; however, its role in interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF), remains largely unknown. This study aims at characterization and targeting of ASS1 deficiency in pulmonary fibrosis. We find that ASS1 was significantly decreased and inversely correlated with fibrotic status. Transcriptional downregulation of ASS1 was noted in fibroblastic foci of primary lung fibroblasts isolated from IPF patients. Genetic manipulations of ASS1 studies confirm that ASS1 expression inhibited fibroblast cell proliferation, migration, and invasion. We further show that the hepatocyte growth factor receptor (Met) receptor was activated and acted upstream of the Src-STAT3 axis signaling in ASS1-knockdown fibroblasts. Interestingly, both arginine-free conditions and arginine deiminase treatment were demonstrated to kill fibrotic fibroblasts, attenuated bleomycin-induced pulmonary fibrosis in mice, as well as synergistically increased nintedanib efficacy. Our data suggest ASS1 deficiency as a druggable target and also provide a unique therapeutic strategy against pulmonary fibrosis.

• Authors: Ji-Min Li, David C Yang, Justin Oldham, Angela Linderholm, Jun Zhang, Jun Liu, Nicholas J Kenyon, Ching-Hsien Chen
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 29 Issue 4 Pg. 1487-1500 (04 07 2021) ISSN: 1525-0024 [Electronic] United States
• PMID: 33508432 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• STAT3 Transcription Factor
• Bleomycin
• Arginine
• MET protein, human
• Proto-Oncogene Proteins c-met
• src-Family Kinases
• Hydrolases
• arginine deiminase
• Argininosuccinate Synthase

Topics

• Animals
• Arginine (genetics)
• Argininosuccinate Synthase (genetics)
• Bleomycin (toxicity)
• Cell Movement (genetics)
• Cell Proliferation (genetics)
• Citrullinemia (genetics, pathology, therapy)
• Female
• Fibroblasts (drug effects)
• Gene Expression Regulation, Enzymologic (genetics)
• Humans
• Hydrolases (pharmacology)
• Lung (pathology)
• Male
• Mice
• Primary Cell Culture
• Proto-Oncogene Proteins c-met (genetics)
• Pulmonary Fibrosis (chemically induced, genetics, therapy)
• STAT3 Transcription Factor (genetics)
• src-Family Kinases