From Reactive Oxygen Species to Organelle Stress and Innate Immunity in Dry Eye Disease

Abstract

Dry eye disease (DED) is a complex, multifactorial condition in which oxidative stress is increasingly recognized as a recurrent feature of ocular-surface dysfunction and as a signaling hub linking environmental stress, organelle dysfunction, innate immunity, and regulated cell death. Mitochondrial and endoplasmic-reticulum dysfunction, failure of endogenous antioxidant systems, and increased production of reactive oxygen species (ROS) can occur in response to tear hyperosmolarity, desiccating stress, aging, and other injuries. These changes activate redox-sensitive signaling pathways such as Nrf2/Keap1, SIRT3–TXNIP–NLRP3, and SLC7A11/GPX4, linking mitochondrial injury and lipid peroxidation to inflammasome activation, ferroptosis, pyroptosis, and epithelial barrier disruption. Damage to the tear film causes persistent inflammation that further damages the ocular surface. This narrative review examines oxidative stress in DED through the lens of redox checkpoints rather than a single pathogenic mechanism. We incorporate up-to-date evidence on organelle stress, antioxidant signaling, innate immune activation, and regulated cell death, and discuss their crosstalk to highlight therapeutically actionable nodes. We focus on newer redox-modulating and mitochondria-targeted strategies, while critically considering the overrepresentation of preclinical evidence, the limited validation of oxidative biomarkers, and the translational barriers that currently keep mechanism-based antioxidant therapy out of routine clinical care for patients with diverse clinical phenotypes of DED.