Non-coding RNA regulatory networks in dry eye disease: implications for pathogenesis and precision therapeutics

Dry eye disease (DED) is a prevalent multifactorial disorder of the ocular surface, characterized by tear film instability, hyperosmolarity, inflammation, and neurosensory dysfunction. Non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, have emerged as critical regulators of post-transcriptional networks governing inflammation, immune cell remodeling, regulated cell death, and epithelial barrier integrity. Evidence indicates that ncRNA dysregulation in DED varies across tissue compartments and disease subtypes, including aqueous-deficient, evaporative, and Sjögren's syndrome-associated forms. Notably, miR-146a, miR-31-5p, and miR-21-5p represent well-supported candidates, whereas lncRNAs and circRNAs are largely emerging mechanisms requiring further validation.This review synthesizes findings from tears, extracellular vesicles, corneal and conjunctival tissues, blood, and lacrimal glands, integrating ncRNA-mediated regulatory pathways into a hierarchical framework of pathogenic networks. We highlight methodological challenges, including sample variability, limited human validation, and heterogeneity across studies, which constrain translation. Current preclinical therapeutic approaches focus on antisense oligonucleotides, vector-mediated ncRNA delivery, and stem cell-derived or engineered extracellular vesicles, aiming to modulate inflammatory signaling, epithelial survival, and immune homeostasis.Overall, ncRNAs offer a mechanistic and translational framework for precision diagnosis and subtype-specific intervention in DED. Future work should prioritize rigorous functional validation, longitudinal cohort studies, and optimized ocular delivery systems to advance ncRNA-based biomarkers and therapeutics toward clinical application.