@article{a96b03ccb0bc498187568952c9e90d0b,
title = "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.",
keywords = "arginine, ASS1, fibroblasts, MET signaling, pulmonary fibrosis",
author = "Li, {Ji Min} and Yang, {David C.} and Justin Oldham and Angela Linderholm and Jun Zhang and Jun Liu and Kenyon, {Nicholas J.} and Chen, {Ching Hsien}",
note = "Funding Information: The authors thank Dr. Richart Harper and Ms. Elena E. Foster (Department of Internal Medicine, UC Davis) for collection of lung tissue samples; Dr. Ssu-Wei Hsu (Integrative Pathobiology, UC Davis) and Ms. Wen-Hsin Chang (Institute of Molecular Medicine, College of Medicine, National Taiwan University) for bioinformatics and statistical support; Ms. Lisa Franzi, Dr. Szu-Jung Chen, Ms. Shenwen Gu, and Ms. Linhui Li (Department of Internal Medicine, UC Davis) for assistance with the animal experiments; as well as the UC Davis Comprehensive Cancer Center Biorepository for pathology support. This work was supported by the California UCOP grants Tobacco-Related Disease Research Program (TRDRP 27KT-0004 and 28IR-0061), the NIH grants (NHLBI R01HL146802, 1K23HL138190, and T32 HL007013), and the DoD PRMRP grant W81XWH2110086 (#PR202411). Conception and design, J.-M.L. and C.-H.C.; development of methodology, J.-M.L. D.C.Y. and C.-H.C.; acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.), J.-M.L. D.C.Y. J.O. A.L. J.Z. N.J.K. and C.-H.C.; analysis and interpretation of data (e.g. statistical analysis, biostatistics, computational analysis), J.-M.L. D.C.Y. A.L. J.Z. and C.-H.C.; writing, review, and/or revision of the manuscript, J.-M.L. D.C.Y. J.L. and C.-H.C.; administrative, technical, or material support (i.e. reporting or organizing data, constructing databases), J.O. N.J.K. and C.-H.C.; study supervision, C.-H.C. The authors declare no competing interests. Funding Information: The authors thank Dr. Richart Harper and Ms. Elena E. Foster (Department of Internal Medicine, UC Davis) for collection of lung tissue samples; Dr. Ssu-Wei Hsu (Integrative Pathobiology, UC Davis) and Ms. Wen-Hsin Chang (Institute of Molecular Medicine, College of Medicine, National Taiwan University) for bioinformatics and statistical support; Ms. Lisa Franzi, Dr. Szu-Jung Chen, Ms. Shenwen Gu, and Ms. Linhui Li (Department of Internal Medicine, UC Davis) for assistance with the animal experiments; as well as the UC Davis Comprehensive Cancer Center Biorepository for pathology support. This work was supported by the California UCOP grants Tobacco-Related Disease Research Program ( TRDRP 27KT-0004 and 28IR-0061 ), the NIH grants ( NHLBI R01HL146802 , 1K23HL138190 , and T32 HL007013 ), and the DoD PRMRP grant W81XWH2110086 ( #PR202411 ). ",
year = "2021",
doi = "10.1016/j.ymthe.2021.01.028",
language = "English (US)",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
}