Lacritin (LACRT) is a tear-derived growth factor that modulates secretion and maintains ocular surface homeostasis through multiple signaling mechanisms 1. Functionally, lacritin stimulates β-hexosaminidase secretion from lacrimal gland acinar cells 2 and exhibits mitogenic activity at the corneal epithelium 1. Mechanistically, lacritin binds to the corneal epithelial cell surface proteoglycan syndecan-1, a process requiring heparanase-mediated exposure of the binding site 3. This interaction triggers rapid signaling through NFAT and mTOR pathways 1, transiently accelerates macroautophagy to restore cellular homeostasis 4, and activates pertussis toxin-sensitive and FOXO-dependent signaling for epithelial healing 3. Clinically, lacritin is selectively deficient in dry eye disease, with tissue transglutaminase-dependent cross-linking reducing monomeric lacritin quantity and syndecan-1 affinity 4. Elevated tear lacritin levels, alongside lysozyme and alpha-2-glycoprotein-1, serve as biomarkers distinguishing Graves' disease patients with orbitopathy from those without 5. Therapeutic approaches using thermo-responsive lacritin fusion proteins show promise for treating dry eye disease by enhancing tear secretion in animal models 2, with phase 2 clinical trials underway 3.