Natural Asp-tRNA Synthetase Fragment Targets Myofibroblasts to Abrogate Tissue Fibrosis

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.