Natural Asp-tRNA synthetase fragment targets myofibroblasts to abrogate tissue fibrosis
Year: 2026
Type: article
Abstract: Fibrosis remains a major global health challenge with limited therapies that only slow disease progression. While the aminoacyl-tRNA synthetase (aaRS) family is known to utilize evolutionarily appended domains as extracellular signaling molecules, their role in regulating the homeostasis of the fibrotic process is poorly defined. We identify a natural proteolytic fragment of aspartyl-tRNA synthetase (DARS), termed DARS-N1, that selectively triggers apoptosis in myofibroblasts by targeting latent-transforming growth factor beta binding protein 1 (LTBP-1) on the extracellular matrix (ECM). This active N-terminal fragment of DARS reduces focal adhesion kinase (FAK) activation in undifferentiated fibroblasts and myofibroblasts, while only myofibroblasts exhibit inadequate cell-matrix attachment leading to loss of anchorage-dependent survival and promotion of apoptosis. We utilized ATYR0101, a therapeutic form of DARS-N1 engineered for extended serum exposure, to demonstrate anti-fibrotic activity in lung (bleomycin). Spatial transcriptomics analysis showed that ATYR0101 activates a restorative program promoting the return to a healthy state. These findings highlight ATYR0101's potential as a transformative therapy for disrupting the process of chronic tissue fibrosis.
Source: Journal of Biological Chemistry
Authors: Ryan A. Adams, Ying-Ting Wang, Alison G. Barber, Kristina Hamel, Andrew Imfeld, Luke Burman, Kaitlyn Rauch, Yeeting E. Chong, Angelica Villanueva, Lauren Guy, Wayne Liu, Crystal Manzo, Sofia Klopp-Savino, Clara Polizzi, Jasmine Stamps, Max Pastenes, Honglei Tian, Chun Po Fung, Yingyi Zhang, Kwok Wa Hugo Ho, Bruno Sangiorgi, Blythe Dillingham, Tarsis F. Brust, Kyle P. Chiang, Zhenguo Wu, Zhiwen Xu, Christoph Burkart, Leslie A. Nangle
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,430
OpenAlex ID: W7214917535