A comprehensive review of tear fluid proteome alterations in dry eye disease: Insights into pathophysiology and biomarker potential

The tear fluid is a highly specialized and dynamic biofluid composed of proteins, lipids, mucins, and electrolytes that is essential for maintaining ocular surface integrity, immune defense, and tear film stability. Growing evidence from tear proteomic studies demonstrates extensive alterations in protein composition in dry eye disease (DED), reflecting a complex interplay between local ocular surface pathology and systemic inflammatory influences. This review summarizes proteomic findings from 50 published studies to identify tear proteins that are consistently upregulated or downregulated in DED and to interpret their biological relevance within the context of ocular surface homeostasis. Across studies, proteins upregulated in DED tears predominantly reflect activation of acute-phase and inflammatory pathways, including S100A8/A9, ORM1, APOA2, and proinflammatory cytokines, as well as oxidative stress responses and epithelial remodeling processes. In contrast, downregulated proteins include key protective and homeostatic tear components such as lactoferrin, lysozyme, lipocalin-1, lacritin, and secretoglobins, along with proteins involved in immune transport, epithelial structure, and lipid metabolism that are critical for tear film stability. Overall, these proteomic shifts indicate activation of stress and inflammatory pathways that may perpetuate epithelial barrier damage and tear film instability in DED. By integrating proteomic data across diverse methodologies, this review highlights convergent biological pathways underlying DED pathophysiology and suggests the potential of tear-based protein panels as biomarkers for disease stratification, monitoring, and therapeutic targeting. • This review summarizes findings from 50 studies on tear protein alterations in DED. • Categorizes altered tear proteins by function and ocular surface pathology • Provides insight into mechanisms underlying tear film dysregulation in DED • Fourteen upregulated and ten downregulated proteins show strong reproducibility • Standardization is essential for translating tear proteomics into clinical biomarkers