Autophagy–Ferroptosis Crosstalk in Dry Eye Disease: Context-Dependent Regulation of Ocular Surface Homeostasis

Dry eye disease (DED) exposes the ocular surface to persistent hyperosmolar, oxidative, metabolic, and inflammatory stress that may increase susceptibility to ferroptosis. Whether autophagy promotes or limits ferroptotic injury in DED remains unresolved. This review critically evaluates evidence from corneal and conjunctival epithelia, lacrimal glands, and meibomian glands, using non-ocular models only to interpret mechanisms not yet resolved in ocular tissues. We propose a threshold-balance framework in which autophagy has context-dependent effects. Ferritinophagy, lipophagy, and impaired autophagic flux can expand the labile iron pool, mobilize peroxidizable lipids, and promote lipid peroxidation. Conversely, intact autophagic–lysosomal flux and mitophagy can remove damaged cargo, limit mitochondrial oxidative stress, and preserve membrane antioxidant defenses. The balance between these processes may determine whether stressed ocular-surface cells adapt or progress toward ferroptotic injury, with consequences for epithelial barrier integrity, tear-film homeostasis, glandular secretion, and inflammation. Studies combining autophagy-related pathway perturbation with ferroptosis-related outcomes are concentrated in ocular-surface epithelial models, whereas this relationship has been less directly examined in lacrimal and meibomian tissues. Establishing causality will require flux-aware measurements, targeted pathway perturbation, tissue-resolved models, and functional validation in human samples. Such studies should clarify when and where autophagy–ferroptosis crosstalk is therapeutically actionable in DED.