{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T12:52:23Z","timestamp":1793105543535,"version":"4.5.0"},"reference-count":73,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"789","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,3,12]]},"abstract":"<jats:p>\n                    Interstitial lung disease (ILD) consists of a group of immune-mediated disorders that can cause inflammation and progressive fibrosis of the lungs, representing an area of unmet medical need given the lack of disease-modifying therapies and toxicities associated with current treatment options. Tissue-specific splice variants (SVs) of human aminoacyl-tRNA synthetases (aaRSs) are catalytic nulls thought to confer regulatory functions. One example from human histidyl-tRNA synthetase (HARS), termed HARS\n                    <jats:sup>WHEP<\/jats:sup>\n                    because the splicing event resulted in a protein encompassing the WHEP-TRS domain of HARS (a structurally conserved domain found in multiple aaRSs), is enriched in human lung and up-regulated by inflammatory cytokines in lung and immune cells. Structural analysis of HARS\n                    <jats:sup>WHEP<\/jats:sup>\n                    confirmed a well-organized helix-turn-helix motif. This motif bound specifically and selectively to neuropilin-2 (NRP2), a receptor expressed by myeloid cells in active sites of inflammation, to inhibit expression of proinflammatory receptors and cytokines and to down-regulate inflammatory pathways in primary human macrophages. In animal models of lung injury and ILD, including bleomycin treatment, silicosis, sarcoidosis, chronic hypersensitivity pneumonitis, systemic sclerosis, and rheumatoid arthritis\u2013ILD, HARS\n                    <jats:sup>WHEP<\/jats:sup>\n                    reduced lung inflammation, immune cell infiltration, and fibrosis. In patients with sarcoidosis, efzofitimod treatment resulted in down-regulation of gene expression for inflammatory pathways in peripheral immune cells and stabilization of inflammatory biomarkers in serum after steroid tapering. We demonstrate the immunomodulatory activity of HARS\n                    <jats:sup>WHEP<\/jats:sup>\n                    and present preclinical data supporting ongoing clinical development of the biologic efzofitimod based on HARS\n                    <jats:sup>WHEP<\/jats:sup>\n                    in ILD.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adp4754","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T13:58:22Z","timestamp":1741787902000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":16,"title":["A human histidyl-tRNA synthetase splice variant therapeutic targets NRP2 to resolve lung inflammation and fibrosis"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6953-7998","authenticated-orcid":true,"given":"Leslie A.","family":"Nangle","sequence":"first","affiliation":[{"name":"aTyr Pharma, San Diego, CA 92121, 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