Conventional management of dry eye disease (DED) often fails to arrest the progressive loss of corneal epithelial cells, making therapeutic management challenging. Emerging evidence points to ferroptosis, an iron-dependent form of regulated cell death, as a central driver of this ocular surface damage. This review provides a comprehensive dissection of the molecular networks driving ferroptosis in DED, delineating how dysregulation of iron metabolism, pathological accumulation of lipid peroxides, and collapse of the redox-inflammation cycle synergistically precipitate cell death. Building upon this mechanistic framework, an integrated therapeutic landscape targeting three distinct axes is outlined. Strategies to control the lipid peroxidation axis are first examined by repurposing thiazolidinediones as enzymatic inhibitors and by addressing the complex dual role of polyunsaturated fatty acids. Methods to reinforce the antioxidant shield are then discussed through selenium-based modulation of glutathione peroxidase 4 (GPX4) and precision mitochondria-targeted interventions. Finally, the restoration of iron homeostasis is highlighted, emphasizing the frequently overlooked potential of physiological chelators, such as lactoferrin, to sequester excess iron. The barriers to clinical translation are addressed, advocating for a paradigm shift towards biomarker-driven precision medicine and the development of advanced ocular drug delivery systems. By bridging biological insights with clinical realities, this review offers a roadmap for developing next-generation, disease-modifying therapies for DED. • Ferroptosis is a key driver of ocular surface damage in dry eye disease. • TZDs inhibit ACSL4 to block lipid peroxidation as a disease-modifying DED therapy. • Lactoferrin acts as a physiological iron chelator to restore ocular iron balance. • Mitochondria-targeted antioxidants and Selenium reinforce the GPX4 redox shield. • Biomarkers and advanced delivery are key for clinical translation.
Yang et al. (Wed,) studied this question.