Regulated Necrosis in Glaucoma: Focus on Ferroptosis and Pyroptosis

Glaucoma is one of the most common causes of irreversible blindness worldwide. This neurodegenerative disease is characterized by progressive and irreversible damage to retinal ganglion cells (RGCs) and optic nerves, which can lead to permanent loss of peripheral and central vision. To date, maintaining long-term survival of RGCs using traditional treatments, such as medication and surgery, remains challenging, as these do not promote optic nerve regeneration. Therefore, it is of great clinical and social significance to investigate the mechanisms of optic nerve degeneration in depth and find reliable targets to provide pioneering methods for the prevention and treatment of glaucoma. Regulated necrosis is a form of genetically programmed cell death associated with the maintenance of homeostasis and disease progression in vivo. An increasing body of innovative evidence has recognized that aberrant activation of regulated necrosis pathways is a common feature in neurodegenerative diseases, such as Alzheimer's, Parkinson's, and glaucoma, resulting in unwanted loss of neuronal cells and function. Among them, ferroptosis and pyroptosis are newly discovered forms of regulated cell death actively involved in the pathophysiological processes of RGCs loss and optic nerve injury. This was shown by a series of in vivo and in vitro studies, and these mechanisms have been emerging as a key new area of scientific research in ophthalmic diseases. In this review, we focus on the molecular mechanisms of ferroptosis and pyroptosis and their regulatory roles in the pathogenesis of glaucoma, with the aim of exploring their implications as potential therapeutic targets and providing new perspectives for better clinical decision-making in glaucoma treatment.