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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

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

Authors: Li, Ji-Min; Yang, David C; Oldham, Justin; Linderholm, Angela; Zhang, Jun; Liu, Jun; Kenyon, Nicholas J; Chen, Ching-Hsien

Published In Mol Ther, (2021 04 07)

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.

PubMed ID: 33508432 Exiting the NIEHS site

MeSH Terms: Animals; Arginine/genetics; Argininosuccinate Synthase/genetics*; Bleomycin/toxicity; Cell Movement/genetics; Cell Proliferation/genetics; Citrullinemia/genetics; Citrullinemia/pathology; Citrullinemia/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; Pulmonary Fibrosis/genetics; Pulmonary Fibrosis/therapy*; STAT3 Transcription Factor/genetics*; src-Family Kinases

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