Ferroptosis and retinal ganglion cell death in glaucoma: Mechanisms and therapeutic approaches

Glaucoma represents a predominant worldwide etiology of permanent vision impairment; it is clinically manifested through progressive neuronal atrophy in retinal ganglion cells (RGCs) and is accompanied by axonal degeneration in the optic pathway. Given the limited efficacy of conventional intraocular pressure-lowering therapies in halting RGC degeneration, the exploration of novel neuroprotective strategies has become imperative. An increasing amount of research emphasizes the pathogenic role of ferroptosis, a metal ion-associated programmed cellular demise mechanism recently implicated in neurodegenerative cascades, as a pivotal executor of RGC demise and putative central mechanism in glaucomatous pathology. This comprehensive review systematically examines the mechanistic interplay between ferroptosis and established contributors to glaucomatous optic neuropathy, including oxidative stress, mitochondrial dysfunction, glutamate excitotoxicity, and neuroinflammation. We provide evidence demonstrating that retinal ferroptosis is associated with the death of RGCs and discuss current therapeutic strategies to mitigate retinal ferroptosis, including treatments with natural products and gene therapy. Furthermore, by understanding ferroptosis, we provide insights into potential therapeutic targets and offer valuable directions for future research and clinical applications.