Ferroptosis in retinal neurodegeneration: mechanistic vulnerability, therapeutic targeting, and translational barriers.

Authors

Guangguang Wu, Suyu Wang, Ziyi Chen, Jiajun Li, Keran Li

Published in

Frontiers in medicine. Volume 13. Pages 1890483. Epub Sep 16, 2026.

Abstract

Progressive retinal neurodegeneration remains a major therapeutic challenge in ophthalmology because structural and functional loss may continue despite control of the primary insult, including intraocular pressure reduction in glaucoma, metabolic management in diabetic retinopathy, or suppression of acute inflammatory activity. Ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid peroxidation and insufficient antioxidant buffering, has emerged as a potential mechanism linking metabolic stress, ischemic injury, excitotoxicity, and neuroinflammatory signaling to sustained retinal neurovascular unit damage. In this review, we synthesize current evidence supporting ferroptosis-related vulnerability in retinal neurodegenerative diseases. Particular emphasis is placed on expansion of the labile iron pool, PUFA-phospholipid remodeling, dysfunction of the System Xc⁻/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis, and multicellular amplification within the neuro-glial-microvascular unit. We further compare disease-specific evidence in glaucoma, diabetic retinopathy, and selected optic nerve injury contexts, emphasizing that causal validation remains uneven across models, cell types, and disease stages. From a translational perspective, we discuss why anti-ferroptotic strategies face distinct ophthalmic barriers, including limited retinal access, insufficient local exposure, short intraocular residence, and safety constraints associated with chronic modulation of iron and redox metabolism. Finally, we evaluate emerging enabling strategies, including nanocarrier-based delivery, long-acting gene modulation, and biomarker frameworks integrating ocular fluids, imaging, multi-omics, and artificial intelligence. Ferroptosis-targeted neuroprotection is therefore best viewed as a disease- and stage-dependent translational framework rather than a universal therapeutic solution.

PMID:
42819585
Bibliographic data and abstract were imported from PubMed on 02 Oct 2026.

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