Emerging mechanisms in dry eye disease: apoptosis-associated tear MicroRNAs and toxicant-related alterations of the glycocalyx and lipid rafts

Background Dry eye disease (DED), a multifactorial condition of the ocular surface, is marked by disruption of tear film homeostasis that can result in ocular discomfort, visual impairment, and potential epithelial damage. Its high prevalence and impact on quality of life and healthcare utilization underscore the need to better understand its underlying mechanisms. Although current research has clarified several key contributors, including tear film instability, ocular surface inflammation, and neural dysfunction, the complex pathophysiology of DED remains only partly understood. Moreover, new mechanistic insights are needed to advance diagnostic and therapeutic approaches. Hypothesis This article highlights three emerging and underexplored mechanisms that may contribute to DED, based on a combination of disease-associated observations, indirect evidence, and mechanistic inference: (i) apoptosis-related tear microRNAs (miRNAs) as potential regulators of epithelial damage, (ii) ocular surface glycocalyx alterations potentially associated with environmental pollutants, and (iii) lipid raft disruption as a plausible mediator of toxicant-induced responses in ocular surface cells. Supporting evidence First, apoptosis-related miRNAs in tears, traditionally viewed as potential biomarkers of the disease, are discussed as candidate regulators of epithelial damage through modulation of apoptotic pathways, although direct evidence in DED causation/development remains limited. Second, glycocalyx alterations potentially associated with environmental pollutants, such as airborne nanoparticles and reactive volatile compounds, are considered. This consideration draws in part on findings from non-ocular and non-DED systems. Third, lipid raft disruption is presented as a plausible but as yet untested mechanism in the context of the ocular surface and DED, potentially linking toxicant exposure to downstream cellular responses. Conclusion By distinguishing between established knowledge, disease-associated findings, and forward-looking hypotheses, this work aims to broaden current perspectives on DED pathophysiology and suggest novel directions for future research.