Starting from the posterior segment of the eye, the retina stands as the light-sensitive neural tissue lining the back surface of the eye. This tissue enjoys immune privilege, housing a defense system comprising retinal immune cells and the complement system [10]. Under normal aging conditions, the retina undergoes low-grade activation capable of eliminating products of oxidative metabolism. Nonetheless, there are cases in which an unbalanced equilibrium between oxidative metabolism and antioxidant defense may cause pathologic situations in the eye.

Glaucoma is a neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs) and optic nerve damage in which oxidative stress may play a significant role in its pathogenesis and progression. In glaucoma, there is a complex relationship between intraocular pressure (IOP) and oxidative stress. The elevated IOP typically found in hypertensive glaucoma can be, on the one side, the reason for mechanical damage and loss of RGC, and on the other side may contribute to enhanced oxidative stress through impaired blood flow, inflammatory response, and mitochondrial dysfunction [11, 12]. Mitochondrial dysfunction is central to the role of oxidative stress in glaucoma. RGCs and other retinal cells in glaucoma exhibit mitochondrial abnormalities, including reduced membrane potential and impaired respiratory chain function, leading to increased ROS production [13]. Moreover, glaucomatous eyes often have impaired antioxidant defense mechanisms; thus, decreased levels of endogenous antioxidants, such as glutathione, superoxide dismutase, and catalase, leave cells vulnerable to oxidative damage. This imbalance between ROS production and antioxidant capacity contributes to the accumulation of oxidative stress in the glaucomatous eye [14]. Oxidative stress also induces inflammatory responses in the retina and optic nerve. Activation of inflammatory pathways produces proinflammatory cytokines and chemokines, exacerbating neuronal damage and contributing to RGC apoptosis and optic nerve degeneration [15]. Moreover, oxidative stress promotes neurodegeneration by damaging cellular components. ROS-mediated DNA damage can lead to mutations and cell death, while oxidative modification of proteins impairs their function and promotes apoptotic signaling pathways. Lipid peroxidation, initiated by ROS, disrupts cell membranes and compromises neuronal integrity [16]. Conversely, oxidative stress can also influence IOP levels in glaucoma by impairing the function of the trabecular meshwork, the tissue responsible for regulating the outflow of aqueous humor from the eye [17]. Dysfunction of the trabecular meshwork can lead to increased resistance to aqueous outflow and elevated IOP. Oxidative stress may directly induce damage to RGCs and their axons, thus disrupting neurovascular coupling and impairing the production of nitric oxide (NO), a key regulator of aqueous humor dynamics [18]. Dysregulation of NO signaling can contribute to alterations in IOP homeostasis.

If mitochondrial dysfunction can directly affect retinal cells in glaucoma, in additional retinal dystrophies characterized by pathological vessel proliferation, dysregulated ROS production due to the anomalous growth of leaky vessels in the posterior segment of the eye leads to retinal cell degeneration [19]. The oxygen-induced retinopathy (OIR) model is commonly used to mimic retinopathy of prematurity (ROP) in preterm infants, but pathologically, it displays similar features to adult retinopathies, including proliferative diabetic retinopathy (PDR) and age-related macular degeneration (AMD). OIR is generated through early exposure of neonatal mice to 75% oxygen, followed by a return to room air. Hyperoxia leads to the regression of blood vessels from the central retina, in which endothelial cell apoptosis triggered by oxidative stress is implicated in vaso-obliteration. Ischemia-induced microvascular abnormalities create a hypoxic condition, activating the proangiogenic pathway and forming new blood vessels that may protrude into the vitreous. The OIR retina provides an excellent model for studying proliferative diseases because its pathological angiogenesis resembles human diseases in which retinal cell degeneration can be indirectly driven by hypoxia-induced retinal vessel growth [20]. Among proliferative retinopathies mimicked by the OIR model, ROP is characterized by abnormal vascularization due to preterm birth [21]. The exposure of the still incompletely vascularized retina to the relatively hyperoxic extrauterine environment induces the downregulation of proangiogenic factors, interrupting retinal vascularization [22]. Indeed, a newborn faces oxidative stress at birth because of the rapid transition from the low-oxygen environment in the womb to the higher oxygen levels outside. During this period, the newborn is vulnerable to oxidative stress due to the underdeveloped efficiency of its antioxidant defenses. In the subsequent weeks, the increasing metabolic demands of the oxygen-deprived retina cause ongoing hypoxia, which stimulates the production of proangiogenic factors and results in harmful blood vessel growth.

Among adult neovascular diseases, PDR represents the most advanced stage of DR, characterized by thin and weak blood vessels whose bleeding can cause scar tissue, leading to retinal detachment [23]. Several factors contribute to the pathogenesis of PDR; however, oxidative stress and inflammatory processes are major. In PDR, hyperglycemia is a significant amplifier of oxidative stress, causing dysregulation of cell metabolism and limiting antioxidant defenses [24]. Epigenetic changes induced by hyperglycemia suppress the body’s antioxidant defense mechanisms, resulting in an imbalance between ROS removal and production. The excessive build-up of ROS leads to mitochondrial damage, cell death, inflammation, lipid peroxidation, and structural and functional changes in the retina. Current treatments for PDR focus only on the later stages, particularly the phase involving abnormal blood vessel growth. However, oxidative stress-related abnormalities present numerous potential therapeutic targets for developing safe and effective treatments for DR. Therefore, it is crucial to address the early ischemic stages, including oxidative stress.

In addition to DR, neovascular age-related macular degeneration (nAMD) is characterized by the abnormal growth of choroidal vessels that penetrate the subretinal space through Bruch’s membrane. This choroidal neovascularization (CNV) leads to fluid leakage, which causes significant retinal damage and subsequent cell death [25]. AMD remains the most commonly diagnosed condition, followed by PDR, with both disorders exhibiting similar underlying mechanisms, such as disrupted angiogenic balance and inflammation triggered by oxidative stress. In proliferative retinopathies, blood accumulates between the neurosensory retina and the retinal pigment epithelium (RPE) or between the RPE and the choroid. Blood breakdown products subsequently damage photoreceptors and the RPE, leading to poor vision and blindness. Antioxidants are crucial for protecting cells from oxidative stress, helping to prevent the progression of diseases, and maintaining vision in many age-related eye conditions, especially AMD. Consequently, incorporating micronutrients with strong antioxidant properties can be a promising approach for preventing and treating eye diseases linked to aging [26]. Much work is being performed to address antioxidant therapy for AMD. However, anti-vascular endothelial growth factor (VEGF) therapy remains a major treatment for most eye diseases associated with VEGF-related vessel proliferation [27, 28]. Yet, despite the encouraging outcomes observed with antioxidant compounds in animal studies, two extensive multicenter trials, namely the Age-Related Eye Disease Study (AREDS) and its follow-up AREDS2, did not demonstrate compelling evidence of antioxidant supplementation effectively benefiting individuals with AMD [29, 30].

Oxidative stress also plays a crucial role in the pathogenesis of several hereditary retinal dystrophies, including Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), Stargardt disease, and retinitis pigmentosa (RP).

In LCA and LHON, the mechanisms and contribution of oxidative stress to disease pathogenesis may differ between these conditions. In LCA, oxidative stress may exacerbate retinal cell dysfunction and degeneration caused by genetic mutations, whereas in LHON, oxidative stress is more directly linked to mitochondrial dysfunction and RGC degeneration [31].

LCA is a group of rare inherited retinal disorders characterized by severe visual impairment or blindness at birth or within the first few months of life. Oxidative stress is thought to play a role in the pathogenesis of LCA, particularly in cases where mutations affect genes involved in phototransduction, visual cycle, or retinal development. Specifically, RDH12 gene mutations, associated with a subset of LCA, have been shown to cause oxidative stress. RDH12 is responsible for reducing all-trans-retinal (atRAL) to all-trans-retinol (atROL) in the visual cycle, and mutations in this gene lead to the accumulation of atRAL, which is highly reactive and induces oxidative stress [32, 33]. In LCA, mutations in various genes may lead to dysfunction or degeneration of photoreceptor cells and RPE, which are highly susceptible to oxidative damage due to their high metabolic activity, constant exposure to light, and abundant polyunsaturated fatty acids. Oxidative stress may exacerbate the underlying genetic defects in LCA by causing further damage to retinal cells through mechanisms such as lipid peroxidation, protein oxidation, DNA damage, and mitochondrial dysfunction. Therapeutic strategies to reduce oxidative stress, such as antioxidant supplementation or gene therapy to enhance antioxidant defenses, are being explored as potential treatments for LCA [33].

Oxidative stress is also involved in the development of LHON, primarily through its impact on mitochondrial dysfunction, which ultimately leads to cell death via apoptosis, autophagy, and inflammation [31]. LHON is marked by the degeneration of RGCs and the optic nerve, manifesting as a sudden and typically severe bilateral loss of central vision. This condition is linked to three main mitochondrial DNA (mtDNA) mutations that cause missense mutations in NADH dehydrogenase, a crucial part of a large multienzyme complex responsible for ATP production through electron transfer and oxidative phosphorylation. LHON’s pathological characteristics include small-caliber axonal demyelination and loss, fiber swelling, and abnormal mitochondria. Proposed mechanisms of pathogenesis include reduced ATP synthesis, increased oxidative stress, and impaired glutamate transport, all contributing to RGC dysfunction and, ultimately, leading to apoptotic cell death. Due to the intricate nature of the structural proteins and pathways involved in mitochondrial functions, modern medicine has seen limited progress in developing effective therapies for mitochondrial diseases.

RP is the leading cause of inherited blindness among retinal diseases, with some rare but severe forms beginning as early as 4 years of age due to mutations in the gamma subunit of phosphodiesterase 6 (PDE6). Research in humans and mice has demonstrated that RP initially manifests as the progressive death of photoreceptors, which then triggers the degeneration of cone photoreceptors. Subsequently, alterations in downstream neurons, the surrounding RPE, and blood vessels accompany this process. In RP, prolonged oxidative stress can result in oxidative damage, further hastening the death of cone photoreceptors [34].

Alongside RP, Stargardt macular degeneration is another genetic eye disorder that results in central vision loss due to lipid buildup in the macula. The visual process begins with the photoisomerization of 11-cis-retinal to its all-trans-form, which is then converted back to 11-cis-retinal to regenerate rhodopsin or cone opsins. Despite being crucial for vision, retinal can be highly toxic to cells because of its reactive aldehyde group and ability to diffuse out of the outer segment compartment. To mitigate this toxicity, retinal is sequestered within a protein and reduced to retinol. The ATP-binding cassette transporter ABCA4 is vital for eliminating toxic byproducts, and mutations that impair its function cause an accumulation of retinoid compounds in photoreceptors and RPE cells [35]. These mutations lead to a range of conditions classified as Stargardt disease, which is marked by central vision impairment and the accumulation of lipofuscin and bis-retinoid compounds in the macula. In both RP and Stargardt disease, additional genetic mutations that cause metabolic disturbances or reduce cellular resilience to oxidative stress contribute to the progressive degeneration of photoreceptors and RGCs, ultimately leading to blindness [36].

Transitioning from the retina toward the anterior eye segment, oxidative stress also plays a significant role in the pathogenesis of various ocular surface diseases, the uvea, and the lens, contributing to tissue damage, inflammation, and disease progression.

Conditions such as dry eye disease (DED), blepharitis, and ocular surface inflammation are characterized by disruption of the tear film, inflammation of the ocular surface tissues, and symptoms such as dryness, burning, itching, and redness. Oxidative stress is implicated in the pathogenesis of ocular surface diseases through several mechanisms. Tear film instability and hyperosmolarity in DED can lead to increased production of ROS and oxidative damage to corneal and conjunctival epithelial cells. Inflammation and immune responses on the ocular surface generate ROS as byproducts, contributing to tissue damage and perpetuating the inflammatory cycle [37]. Environmental factors such as ultraviolet (UV) radiation, air pollution, and cigarette smoke exposure can induce oxidative stress and exacerbate ocular surface inflammation. Antioxidant defense mechanisms in tears and ocular surface tissues help counteract oxidative stress, but their efficacy may be overwhelmed in conditions of chronic inflammation or environmental stress. Therapeutic strategies for ocular surface diseases often include interventions to reduce oxidative stress, such as topical antioxidant eye drops, omega-3 fatty acid supplementation, and lifestyle modifications to minimize environmental exposures [38].

Uveitis refers to inflammation of the uveal tract, which includes the iris, ciliary body, and choroid, although inflammation can also involve adjacent ocular structures, such as the retina and optic nerve. Oxidative stress is a key contributor to the pathogenesis of uveitis, amplifying inflammatory responses and causing tissue damage in the affected eye [19]. Inflammatory cells infiltrating the uveal tissues release ROS and reactive nitrogen species (RNS), leading to oxidative damage to endothelial cells, fibroblasts, and other resident cells. Oxidative stress activates nuclear factor kappa B (NF-$\kappa$B) signaling pathways, cytokine production, and leukocyte recruitment, perpetuating the inflammatory cascade. Furthermore, oxidative damage to retinal tissues can contribute to secondary complications of uveitis, such as macular edema, retinal vascular occlusions, and cystoid macular degeneration [39]. Antioxidant therapies, including systemic or intraocular administration of antioxidants such as vitamin C, vitamin E, and glutathione precursors, may help mitigate oxidative stress and reduce inflammation in uveitis [40, 41].

Cataract is a common age-related condition characterized by clouding of the crystalline lens, leading to visual impairment or blindness if left untreated. Oxidative stress is a major contributor to cataract formation, particularly in age-related and oxidative stress-induced cataracts [42]. Accumulation of ROS and oxidative damage to lens proteins, lipids, and DNA disrupts lens transparency and homeostasis, leading to protein aggregation, lens fiber cell disorganization, and, ultimately, cataract formation. Oxidative modification of lens proteins, such as oxidation of sulfhydryl groups and formation of protein-protein crosslinks, alters the structural and functional properties of lens proteins, impairing their solubility and transparency. Environmental factors such as UV radiation, smoking, and exposure to heavy metals exacerbate oxidative stress and increase the risk of cataract development. Antioxidant defense systems in the lens, including glutathione and antioxidant enzymes such as superoxide dismutase and catalase, help maintain redox balance and protect against oxidative damage. Dietary antioxidants, supplementation with vitamins C and E, and lifestyle modifications to reduce oxidative stress (e.g., smoking cessation, UV protection) may help prevent or delay the progression of cataract formation [43].

Myopia is a condition where visual images are focused in front of the retinal plane while the eye is at rest, resulting in blurred distance vision. It is primarily a consequence of excessive axial elongation during the growth of the eye. This elongation can disturb the choroid, leading to a significant decrease in its thickness, as well as a reduction in blood flow and perfusion [44]. The resultant hypoxic state triggers a series of events that induce oxidative stress in eye tissues, including (1) mitochondrial dysfunction, as reduced oxygen levels impair mitochondrial function, ultimately leading to increased ROS production [45]; (2) activation of hypoxia-inducible factor (HIF), a protein that responds to hypoxia and regulates the expression of genes involved in oxidative stress pathways [46]; (3) hypoxia-induced inflammation, which can promote ROS production [46]; (4) endoplasmic reticulum stress, as hypoxia disrupts protein folding in the endoplasmic reticulum, thereby leading to oxidative stress [47].

In this context, it is noteworthy to mention the dual effect of atropine, which is often used to slow myopia progression in children, on extracellular matrix (ECM) production by human scleral (HSF) and choroidal (HCF) fibroblasts. Atropine stimulates ECM production by HSF, likely increasing the rigidity of the sclera and inhibiting its elongation, while it decreases ECM production by HCF, probably enhancing blood perfusion to the surrounding eye tissues, thus reducing oxidative stress and inhibiting axial elongation [48].