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Therapeutic exploitation of ferroptosis pathways in dry eye disease: Opportunities and challenges
Chunhui Yang1, Shuo Yang1, Xingyi Shu1
1Department of Ophthalmology, Changzheng Hospital of Naval Medical University, Shanghai, China.
Abstract:
Conventional management of dry eye disease (DED) often fails to arrest the progressive ocular surface cell damage, 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. Importantly, ferroptosis in DED exhibits marked cell-type specificity across epithelial, glandular, and immune compartments of the ocular surface. 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.
Insights
Ferroptosis, an iron-dependent cell death, drives dry eye disease (DED) progression. Targeting lipid peroxidation, antioxidant defenses, and iron balance offers new therapeutic strategies for DED.
Area of Science:
- Ophthalmology
- Cell Biology
- Biochemistry
Background:
- Dry eye disease (DED) management struggles with progressive corneal cell loss.
- Ferroptosis, a regulated cell death pathway, is increasingly recognized as a key factor in DED pathogenesis.
- Dysregulation of iron metabolism, lipid peroxidation, and redox balance contribute to DED.
Purpose of the Study:
- To dissect the molecular mechanisms of ferroptosis in DED.
- To outline an integrated therapeutic strategy targeting ferroptosis in DED.
- To bridge biological insights with clinical applications for DED treatment.
Main Methods:
- Review of molecular networks driving ferroptosis in DED.
- Analysis of therapeutic strategies targeting lipid peroxidation, antioxidant defense, and iron homeostasis.
- Discussion of clinical translation barriers and precision medicine approaches.
Main Results:
- Ferroptosis is driven by dysregulated iron metabolism, lipid peroxides, and redox-inflammation.
- Therapeutic axes include inhibiting lipid peroxidation (e.g., thiazolidinediones), reinforcing antioxidant defenses (e.g., GPX4 modulation, mitochondria-targeted therapies), and restoring iron homeostasis (e.g., lactoferrin).
Conclusions:
- Targeting ferroptosis pathways offers a promising approach for novel DED therapies.
- Biomarker-driven precision medicine and advanced drug delivery are crucial for clinical translation.
- This review provides a roadmap for developing disease-modifying treatments for DED.
