WARS1 (tryptophanyl-tRNA synthetase 1) is a multifunctional protein with both canonical and immunomodulatory roles. Primarily, it catalyzes aminoacylation of tryptophan to its cognate tRNA, supporting protein synthesis 1. Beyond translation, WARS1 functions as an innate immune activator through two distinct secretion pathways: tryptophan-dependent naked protein secretion and tryptophan-independent plasma membrane vesicle-mediated secretion 2. In extracellular space, secreted WARS1 acts as a ligand for toll-like receptors 2 and 4, triggering proinflammatory responses 3. Disease relevance spans neurodevelopmental and inflammatory conditions. Biallelic WARS1 variants cause autosomal recessive microcephaly, developmental delay, and brain anomalies, with genetic evidence suggesting impaired protein abundance 1. Autosomal dominant variants associate with distal hereditary motor neuropathy 1. In sepsis, elevated plasma WARS1 stratifies critically ill patients with hypercytokinemia and predicts 28-day mortality, particularly in patients without monocytopenia 34. Genome-wide association studies identify WARS1 as causally associated with age-related macular degeneration through tryptophan metabolite pathways 56. In therapeutic contexts, WARS1-overexpressing mesenchymal stem cells demonstrate enhanced immunomodulatory capacity and improved efficacy in psoriasis treatment 7.