Abstract:Dry eye disease (DED) is a multifactorial ocular surface disorder characterized by disruption of tear film homeostasis. Persistent hyperosmolarity, oxidative stress, and inflammation can overwhelm adaptive responses in ocular surface epithelial cells, leading to mitochondrial bioenergetic dysfunction, endoplasmic reticulum proteostasis disturbance, and impaired autophagy-lysosome flux. Mitochondrial injury promotes reactive oxygen species accumulation and mitochondrial DNA (mtDNA) release; endoplasmic reticulum stress disrupts protein folding and secretion; and autophagy-lysosome dysfunction compromises the clearance of damaged organelles. These processes are interconnected and can amplify ocular surface injury through cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling, inflammasome activation, lipid peroxidation, pyroptosis, and ferroptosis, This review summarizes stress-related alterations in mitochondria, the endoplasmic reticulum, and the autophagy-lysosome system in dry eye disease, discusses their functional crosstalk and downstream injury pathways, and evaluates emerging therapeutic strategies aimed at restoring organelle homeostasis.
