Catalase Functions and Glycation: Their Central Roles in Oxidative Stress, Metabolic Disorders, and Neurodegeneration

Abstract

Catalase, a pivotal antioxidant enzyme, plays a central role in converting hydrogen peroxide (H₂O₂) into oxygen and water, thereby safeguarding cells from oxidative damage. In patients with diabetes, obesity, Alzheimer’s disease (AD), and Parkinson’s disease (PD), catalase becomes increasingly susceptible to non-enzymatic glycation, resulting in enzyme inactivation, oxidative stress, and defective mitochondrial function. This review uniquely emphasizes catalase glycation as a converging pathological mechanism that bridges metabolic and neurodegenerative disorders, underscoring its translational significance beyond prior general reviews on catalase function. In patients with metabolic diseases, glycation impairs β-cell function and insulin signaling, while in patients with neurodegeneration, it accelerates protein aggregation, mitochondrial dysfunction, and neuroinflammation. Notably, the colocalization of glycated catalase with amyloid-β and α-synuclein highlights its potential role in protein aggregation and neuronal toxicity, a mechanism not previously addressed. Therapeutically, targeting catalase glycation opens up new avenues for intervention. Natural and synthetic agents can be used to protect catalase activity by modulating glyoxalase activity, heme integrity, or carbonyl stress. Vitamins C and E, along with agents like sulforaphane and resveratrol, exert protection through complementary mechanisms, beyond ROS scavenging. Moreover, novel strategies, including Nrf2 activation and receptor for advanced glycation end products (RAGE) inhibition, are showing promise in restoring catalase activity and halting disease progression. By focusing on glycation-specific mechanisms and proposing targeted therapeutic approaches, this review positions catalase glycation as a novel and clinically relevant molecular target in patients with chronic diseases and a viable candidate for translational research aimed at improving clinical outcomes.

1. Introduction

Catalase is an important enzyme that catalyzes the breakdown of H₂O₂, which is a byproduct of various metabolic processes [1]. Hydrogen peroxide upon accumulation becomes highly toxic, which causes damage to critical biomolecules, such as lipids, proteins, and DNA [2]. Catalase maintains cellular redox homeostasis and prevents oxidative stress-related damage [3]. Given its central role in detoxification, catalase is ubiquitously present in almost all aerobic organisms, including bacteria, plants, and mammals [1]. In mammals, it is predominantly localized in peroxisomes, but is also found in cytosolic and mitochondrial compartments, where it functions in concert with superoxide dismutase (SOD) and glutathione peroxidase (GPx) to ensure the efficient clearance of reactive oxygen species (ROS).

Glycation, a non-enzymatic reaction, takes place between reducing sugars or reactive carbonyl species (RCS) and the free amino groups in proteins, leading to structural and functional impairments [4]. Unlike enzymatic glycosylation, which is a controlled biological process, glycation is a spontaneous and irreversible modification, typically occurring under conditions of hyperglycemia, oxidative stress, and aging. The glycation process follows a stepwise progression, beginning with the Schiff base formation that undergoes Amadori rearrangement to form more stable ketoamine structures [4]. Over time, these intermediates react further through oxidation, dehydration, and cross-linking, resulting in the synthesis of advanced glycation end products (AGEs). Proteins with long half-lives and high lysine/arginine content, such as hemoglobin, albumin, and crystallins, are particularly vulnerable to glycation [5]. Antioxidant enzymes are prime targets due to their functional amino acid residues, which are critical for enzymatic activity. The glycation of catalase diminishes its ability to decompose H₂O₂ efficiently, leading to higher oxidative stress and a cascade of cellular dysfunctions [6].

Glycation-induced modifications of catalase can have profound effects on cellular functions [3]. These molecular disruptions contribute to metabolic disorders like diabetes mellitus and neurodegenerative conditions, such as Alzheimer’s and Parkinson’s diseases. In patients with diabetes, sustained high glucose levels induce the excessive glycation of proteins, including antioxidant enzymes, exacerbating inflammation [7]. Glycated catalase has been detected in pancreatic β-cells, where its inactivation leads to increased ROS levels, mitochondrial stress, and impaired insulin secretion [8]. Similarly, in regard to neurodegenerative diseases, catalase glycation contributes to neuronal dysfunction, the aggregation of misfolded proteins, and neuroinflammation [9]. The pileup of AGEs in the brain may be linked to enhanced oxidative damage and progressive cognitive decline.

Catalase glycation is a significant factor in metabolic and neurodegenerative disorders, leading to higher oxidative stress and inflammation [10]. Given the profound impact of catalase glycation on cellular homeostasis, addressing this modification is crucial for mitigating oxidative stress-related diseases. By preventing catalase glycation, either through the use of antiglycation agents, enzyme stabilizers, or gene-editing approaches, it may be possible to preserve the enzymatic function of catalase, thereby maintaining the redox balance and reducing the disease burden. Additionally, targeting the receptor for advanced glycation end products (RAGE) could disrupt the harmful inflammatory cascades triggered by glycated catalase, offering another approach to therapeutic intervention.

Bioactive compounds with diverse pharmacological effects, including immune regulatory, antitumor, antioxidant, and anti-aging activities, have therapeutic potential [11]. Plant polysaccharides (PPS) are safe bioactive compounds that can be used to treat metabolic disorders, such as cardiovascular disease, diabetes, obesity, and neurological conditions [11]. Future research must focus on refining therapeutic strategies by improving the bioavailability and specificity of antiglycation compounds, enhancing the stability of catalase through molecular engineering, and identifying novel RAGE inhibitors with fewer side effects. Advancements in nanomedicine, personalized medicine, and gene therapy also hold promise for restoring catalase activity and preventing its glycation in susceptible individuals. Ultimately, by effectively targeting catalase glycation, we can significantly reduce oxidative stress, improve metabolic and neurodegenerative disease management, and enhance overall patient outcomes. This highlights the need for continued research and innovation in regard to understanding and mitigating the effects of catalase glycation to pave the way for novel, effective therapeutic interventions.

2. Catalase Functions

Catalase is found in nearly all aerobic organisms and plays an essential role in cellular signaling, aging, disease prevention, and immune regulation (Figure 1) [9,12].

2.1. Antioxidant Defense

Hydrogen peroxide is naturally produced during metabolic activities like respiration and immune responses [13]. However, the excessive accumulation of hydrogen peroxide leads to oxidative stress, damaging essential biomolecules, such as DNA, proteins, and lipids. This damage contributes to aging, inflammation, and chronic diseases, including cardiovascular disorders. Catalase, present in nearly all aerobic cells, acts as a protective barrier, neutralizing H₂O₂ before it becomes toxic [14]. In high-metabolism organs like the liver, brain, and heart, the antioxidant activity of catalase plays an essential role in preventing oxidative injuries (Figure 1) [15]. Without catalase, unchecked ROS buildup could cause cellular dysfunction, cell death, or mutations, ultimately leading to severe health conditions. In therapeutic research, catalase has been explored as a potential treatment for oxidative stress-induced diseases, showing promise in reducing oxidative damage in regard to neurological and cardiovascular conditions [9].

2.2. Regulating the Redox Balance and Cellular Pathways

Beyond its enzymatic function, catalase plays a role in cellular signaling by regulating the redox balance (Figure 1) [12]. The role of ROS as secondary messengers has been shown in regard to various processes, including immune responses, apoptosis, and cellular differentiation [16]. While controlled ROS levels are necessary for these functions, excess ROS can lead to chronic inflammation, aberrant cell proliferation, or degenerative diseases. Catalase ensures that this balance is maintained by preventing excessive oxidative signaling. In cancer biology, abnormal ROS signaling is associated with tumor growth and metastasis [17]. Catalase’s role in reducing oxidative stress makes it a potential target in cancer therapies. Additionally, catalase also affects insulin signaling and glucose metabolism by modulating oxidative stress levels in pancreatic β-cells [18]. The enzyme’s ability to maintain redox homeostasis also contributes to its neuroprotective functions, as neurons are particularly sensitive to oxidative damage. Studies suggest that catalase activity declines with age, leading to imbalances in redox signaling that contribute to neurodegeneration [3]. Moreover, catalase interacts with other antioxidant enzymes to fine tune intracellular ROS levels, ensuring proper cell communication, survival, and adaptation to environmental stressors [19].

2.3. Aging and Longevity

Aging is largely driven by cumulative oxidative stress, which accelerates cellular damage and causes a decline in organ function over time. Catalase alleviates the oxidative burden in mitochondria, where ROS are abundantly produced (Figure 1) [20]. Studies on longevity have shown that increasing catalase activity in mitochondria can extend the lifespan of mice and fruit flies [21]. By preventing oxidative DNA damage, catalase helps maintain genetic stability, reducing the risk of age-related diseases like cancer and neurodegeneration [3]. Additionally, catalase’s role in maintaining protein integrity ensures proper cellular function, delaying the onset of age-related dysfunctions. Aging diminishes mitochondrial functions, and catalase’s ability to protect mitochondria from oxidative damage improves cellular energy production and resilience against age-related decline. Research has also linked catalase activity to stress resistance, suggesting that individuals with higher catalase levels may be better equipped to handle environmental stressors, contributing to increased longevity. Furthermore, the protective role of the enzyme in stem cells helps to maintain the tissue regeneration capacity, a key factor in healthy aging [22]. By reducing chronic inflammation and cellular damage, catalase enhances the overall human health span, ensuring a better quality of life in later years.

2.4. Disease Prevention

In patients with neurodegenerative diseases, including Alzheimer’s and Parkinson’s, excess ROS contribute to neuronal death, protein misfolding, and cognitive decline [23]. Catalase helps mitigate these effects by reducing the oxidative burden in the brain, preserving neuronal integrity, and improving cognitive function (Figure 1) [24]. In patients with cancer, oxidative stress can induce DNA mutations and uncontrolled cell proliferation [25]. By reducing H₂O₂ levels, catalase can minimize genetic mutations, slowing down cancer progression. Studies have shown that cancer cells often have an altered redox balance, making catalase an important factor in tumor suppression [26]. Furthermore, catalase can contribute to cardiovascular health by protecting blood vessels from oxidative damage that leads to hypertension and atherosclerosis [9]. In patients with diabetes, oxidative stress impairs insulin secretion and glucose metabolism, and catalase helps in maintaining pancreatic β-cell function, improving insulin sensitivity and reducing the risk of diabetes complications. The enzyme also supports liver function by preventing oxidative damage associated with fatty liver disease [27]. Overall, catalase’s ability to prevent oxidative stress-related diseases makes it a key target in therapeutic research on conditions linked to chronic inflammation and oxidative damage.

2.5. Immune System Regulation

The immune system relies on ROS as part of its defense mechanism to eliminate pathogens [28]. However, the persistent overproduction of ROS contributes to sustained inflammation and the onset of autoimmune conditions [29]. Catalase plays a critical role in modulating immune responses by preventing oxidative bursts in macrophages and neutrophils (Figure 1) [30]. By controlling ROS levels, catalase helps in preventing excessive tissue damage during infections. In patients with inflammatory diseases, such as rheumatoid arthritis and asthma, catalase alleviates oxidative burden-induced inflammation, providing therapeutic benefits [19]. Additionally, catalase supports immune cell longevity and function, ensuring a strong immune response. In regard to conditions like sepsis, where intense oxidative stress can lead to multiple organ failure, catalase’s protective role becomes even more critical. Research suggests that individuals with higher catalase activity may have stronger immune resilience, reducing their susceptibility to infections and autoimmune diseases [3]. The enzyme’s ability to prevent chronic inflammation also has implications for aging, as persistent low-grade inflammation, known as “inflammaging,” is a major contributor to age-related diseases. By reducing oxidative stress and modulating immune responses, catalase supports overall immune health and improves the body’s ability to combat diseases effectively.

3. Catalase Glycation and Its Molecular Mechanism

3.1. Non-Enzymatic Glycation of Lysine and Arginine Residues

Glycation is a non-enzymatic reaction, whereby reducing sugars like glucose and fructose or reactive dicarbonyl compounds (e.g., methylglyoxal, glyoxal) react with the free amino groups of lysine and the guanidinium groups in arginine [4]. The initial step of glycation involves the reaction of a reducing sugar with the amino group in proteins, leading to the formation of a reversible Schiff base intermediate, which can subsequently rearrange into a more stable Amadori product. Over time, oxidative conditions promote the formation of irreversible AGEs, leading to protein cross-linking, a loss of enzymatic function, and aggregation.

3.2. Molecular Mechanisms of Catalase Glycation

At the molecular level, glycation can affect catalase in several critical ways, including the modification of active site residues, conformational instability, aggregation, and a loss of metal ion coordination [9]. These modifications impair its enzymatic activity, promote oxidative stress, and pave the way for metabolic and neurodegenerative disease pathogenesis [31]. Glycated lysine and arginine residues fail to stabilize the heme group, disrupting the redox cycle that is necessary for catalase activity [12]. This destabilization results in the decreased affinity of the enzyme to hydrogen peroxide, reducing its ability to neutralize ROS effectively. The modified active site residues no longer effectively position H₂O₂ for decomposition, contributing to oxidative stress. Glycation-induced modifications alter intra- and intermolecular interactions within catalase, leading to improper protein folding and aggregation [6]. This makes the enzyme more prone to proteolytic degradation, further diminishing its intracellular levels. In some cases, glycation can induce pro-oxidant behavior, whereby partially inactivated catalase can contribute to the generation of hydroxyl radicals (•OH) under oxidative stress conditions. This exacerbates cellular damage, particularly in tissues vulnerable to oxidative stress, including pancreatic β-cells, neurons, and endothelial cells (Figure 2).

4. Implications of Catalase Glycation in Regard to Disease Pathogenesis

The glycation of catalase leads to structural instability, functional impairment, and aggregation, which exacerbates oxidative stress and inflammatory signaling [10]. In patients with metabolic disorders, such as diabetes, glycated catalase contributes to β-cell dysfunction and insulin resistance by failing to regulate ROS levels efficiently [8]. This promotes mitochondrial damage, lipid peroxidation, and systemic inflammation, further aggravating diabetic complications, such as neuropathy, nephropathy, and retinopathy (Figure 3). Similarly, in patients with neurodegenerative diseases like Alzheimer’s and Parkinson’s, the glycation of catalase exacerbates neuronal oxidative stress and disrupts mitochondrial function, which leads to protein aggregation and neuronal apoptosis [3]. Accumulated AGEs formed from glycated catalase activate RAGE, which triggers a cascade of inflammatory responses, contributing to neuroinflammation and progressive cognitive decline.

4.1. Diabetes Mellitus and Its Associated Complications

One of the primary metabolic conditions affected by catalase glycation is diabetes mellitus. A sustained high glucose level can induce glycation reactions, leading to a decline in catalase activity. The implications of this process include β-cell dysfunction and insulin resistance, leading to metabolic and diabetes-associated complications (Figure 2).

4.1.1. β-Cell Dysfunction

The dysfunction of β-cells is a basic pathological hallmark of type 2 diabetes, often intensified by oxidative stress and chronic hyperglycemia. Among the mechanisms leading to β-cell failure, catalase glycation has a role in amplifying oxidative stress and cellular damage. Under hyperglycemic conditions, catalase undergoes significant structural and functional impairments. The consequent accumulation of ROS within pancreatic β-cells disrupts mitochondrial function, impairing the ATP synthesis required for glucose-stimulated insulin secretion [32]. Excess ROS not only damages mitochondrial membranes and DNA, but also activates pro-apoptotic signaling pathways, culminating in β-cell apoptosis. The loss of functional β-cell mass compromises insulin production and contributes to sustained hyperglycemia, creating a vicious cycle of metabolic dysregulation. Moreover, oxidative stress from catalase glycation further sensitizes β-cells to inflammatory cytokines, amplifying cellular injury [33]. As a result, the progressive decline in β-cell viability and function leads to worsening glucose intolerance and speeds up the onset of diabetes-related complications (Figure 2). Thus, preventing catalase glycation and preserving β-cell antioxidant defenses are critical strategies for improving the outcomes in patients with type 2 diabetes.

4.1.2. Insulin Resistance

Insulin resistance is a pathological condition in which cells in key metabolic tissues, including skeletal muscle, liver, and adipose tissue, fail to respond adequately to circulating insulin, resulting in impaired glucose uptake and elevated blood glucose levels. A central contributor to this impaired insulin sensitivity is oxidative stress, which disrupts the intracellular signaling cascades necessary for insulin action. Under chronic hyperglycemia and metabolic stress, catalase becomes susceptible to non-enzymatic glycation, leading to reduced enzymatic activity and increased oxidative stress [34]. The oxidative burden impairs insulin receptor signaling by altering insulin receptor substrate (IRS) phosphorylation and activating stress-related kinases, such as JNK and IKK-β [35]. These molecular disruptions can alter downstream insulin signaling pathways, promoting insulin resistance. Moreover, the oxidative environment fosters low-grade chronic inflammation, which further disrupts insulin sensitivity. As insulin resistance progresses, glucose homeostasis deteriorates, which contributes to type 2 diabetes progression. Therefore, preserving catalase activity by preventing glycation is crucial for maintaining insulin responsiveness and metabolic health.

4.1.3. End-Organ Damage

In diabetes, end-organ damage is a major consequence of sustained hyperglycemia and heightened oxidative stress, both of which are intensified by catalase glycation. Reduced catalase activity promotes oxidative injury to the vascular endothelium, neurons, glomerular cells, and retinal tissues, thereby accelerating the development of diabetic complications (Figure 2). In the eyes, oxidative stress damages the retinal microvasculature, contributing to diabetic retinopathy. In the kidneys, accumulated ROS harms glomerular filtration structures, resulting in proteinuria and progressive nephropathy. Neurons are also highly susceptible to oxidative stress, and catalase inactivation contributes to the axonal degeneration and sensory deficits seen in diabetic neuropathy [36]. Additionally, oxidative injury to cardiovascular tissues elevates the risk of atherosclerosis, hypertension, and heart failure. The cumulative impact of catalase glycation and elevated ROS levels undermines organ function, exacerbating the severity and progression of diabetes-related complications. Therefore, therapeutic strategies that restore catalase activity or prevent its glycation may offer significant benefits in protecting end-organ function and improving the prognosis of patients with long-standing diabetes.

4.1.4. Diabetic Retinopathy

Diabetic retinopathy is a prevalent microvascular complication of diabetes, driven by prolonged hyperglycemia, persistent oxidative stress, and chronic inflammation [37]. A key factor contributing to the progression of this condition is catalase glycation, which significantly impairs the eye’s antioxidant defenses, resulting in ROS accumulation within retinal tissues. The elevated ROS levels trigger oxidative damage to the retinal microvasculature, compromising the integrity of endothelial cells and pericytes [38]. This leads to capillary leakage, hemorrhage, and the breakdown of the blood–retinal barrier. As the disease advances, ischemic damage to retinal tissue induces the production of the vascular endothelial growth factor (VEGF), resulting in abnormal neovascularization. These fragile new vessels are prone to rupture, exacerbating vision loss. Clinically, diabetic retinopathy can manifest as mild vision disturbances in the early stages, and progress-to-severe visual impairment or blindness if left untreated. The underlying oxidative imbalance, worsened by catalase glycation, highlights the need for antioxidant-based therapeutic strategies to protect retinal function and prevent disease progression.

4.1.5. Diabetic Nephropathy

Diabetic nephropathy is a serious complication of diabetes, characterized by progressive kidney damage, driven by chronic hyperglycemia and persistent oxidative stress [39]. One of the critical molecular contributors to this pathology is catalase glycation, which severely impairs the enzyme’s antioxidant capacity. The resulting accumulation of ROS initiates oxidative damage to glomerular endothelial cells, mesangial cells, and podocytes, which are essential for maintaining normal kidney filtration (Figure 4). Oxidative stress is largely secondary to hyperglycemia-induced metabolic dysregulation; once established, it accelerates inflammation, fibrosis, and further AGE accumulation, thereby amplifying nephropathy progression. Oxidative stress in this scenario also promotes inflammation and activates profibrotic signaling pathways, contributing to extracellular matrix deposition and glomerulosclerosis. Functionally, this damage manifests as glomerular dysfunction, increased permeability, and proteinuria, an early clinical marker of diabetic nephropathy. As the condition progresses, sustained ROS exposure and fibrosis impair kidney function, ultimately leading to chronic kidney disease (CKD) and end-stage renal failure. Preventing catalase glycation or restoring the enzyme’s activity may be crucial in halting the progression of diabetic nephropathy by preserving redox homeostasis and protecting renal structure and function.

4.1.6. Diabetic Neuropathy

Diabetic neuropathy is a debilitating nerve disorder commonly associated with long-term diabetes, resulting from a combination of hyperglycemia, oxidative stress, and vascular impairment [40]. Under hyperglycemic conditions, the resulting oxidative imbalance leads to excessive ROS accumulation in peripheral neurons, triggering mitochondrial dysfunction and impairing ATP production. Mitochondrial damage disrupts calcium homeostasis and promotes the release of pro-apoptotic factors, finally leading to neuronal degeneration [41]. Additionally, the oxidative environment compromises axonal integrity and the myelin structure, impairing nerve conduction and signal transmission. Clinically, this manifests as sensory abnormalities, including chronic pain, tingling, numbness, or a loss of sensation, particularly in the hands and feet. As diabetic neuropathy progresses, it can significantly reduce the patient’s quality of life and increase the risk of foot ulcers and limb amputation. Protecting catalase from glycation and restoring the redox balance are critical therapeutic goals to slow down the progression of diabetic neuropathy.

4.2. Cardiovascular Diseases

Glycated catalase has been implicated in the progression of atherosclerosis, hypertension, and cardiac dysfunction (Figure 5) [42]. The mechanisms through which it contributes to cardiovascular diseases include the following:

4.2.1. Endothelial Dysfunction

Endothelial dysfunction, a key factor in vascular complications of diabetes, is characterized by impaired nitric oxide (NO) production, greater oxidative stress, and vascular inflammation [43]. Catalase glycation exacerbates this condition, leading to greater ROS generation. This oxidative imbalance damages endothelial cells, disrupts vascular homeostasis, and promotes a pro-inflammatory and pro-thrombotic state. Consequently, endothelial dysfunction contributes to hypertension, atherosclerosis, and microvascular complications. The loss of catalase function due to glycation accelerates endothelial cell apoptosis, further impairing vascular repair and regeneration (Figure 5).

4.2.2. Macrophage Activation and Foam Cell Formation

Macrophage activation and foam cell formation are important events in atherosclerosis, which are exacerbated by catalase glycation in patients with diabetes [44]. Glycated catalase loses its antioxidant function, increasing oxidative stress and ROS accumulation [10]. This promotes macrophage activation, triggering pro-inflammatory cytokine release and enhancing low-density lipoprotein (LDL) oxidation. Oxidized LDL is engulfed by macrophages via scavenger receptors, leading to foam cell formation (Figure 5). These lipid-laden foam cells accumulate in arterial walls, forming plaques that contribute to vascular inflammation, endothelial dysfunction, and atherosclerosis progression. Impaired catalase activity accelerates this process, increasing the chances of cardiovascular diseases in diabetic patients.

4.2.3. Myocardial Fibrosis

Myocardial fibrosis is a pathological condition characterized by excessive collagen deposition in the heart, leading to stiffness, impaired cardiac function, and heart failure [45]. Reduced catalase activity promotes fibroblast activation, extracellular matrix remodeling, and excessive collagen synthesis. This oxidative imbalance also triggers inflammatory signaling, enhancing profibrotic cytokine production. Over time, myocardial fibrosis contributes to diastolic dysfunction, reduced contractility, and an increased risk of heart failure in diabetic patients, worsening cardiovascular complications associated with metabolic disorders (Figure 5).

4.2.4. Obesity and Metabolic Syndrome

Obesity and metabolic syndrome (MetS) are characterized by insulin resistance, chronic inflammation, and oxidative stress (Figure 6) [46]. A major consequence of these metabolic disturbances is the disruption of redox homeostasis, wherein the balance between ROS production and the antioxidant defense is impaired. This imbalance contributes to cellular dysfunction, promoting disease progression. Moreover, excessive fat accumulation leads to mitochondrial dysfunction and NADPH oxidase activation, generating high levels of ROS. Chronic low-grade inflammation, common in obesity, further amplifies oxidative stress through cytokine-induced ROS production. As a result, natural antioxidant mechanisms, including enzymatic systems like catalase, SOD, and glutathione peroxidase, become overwhelmed. Post-translational modifications, such as glycation, further impair the efficiency of these enzymes, weakening cellular protection against oxidative damage.

4.3. Catalase Glycation in Neurodegenerative Disorders

4.3.1. Alzheimer’s Disease (AD)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuronal loss, and the accumulation of amyloid-beta (Aβ) plaques and tau tangles (Figure 7) [47]. In patients with AD, catalase undergoes glycation, which impairs its function and exacerbates oxidative stress.

Glycated CAT and Oxidative Stress in AD

In patients with AD, chronic hyperglycemia and oxidative conditions promote catalase glycation, leading to its reduced enzymatic activity. Dysfunctional catalase can accelerate neuronal degeneration, mitochondrial dysfunction, and synaptic loss, key hallmarks of AD pathology. Moreover, glycated catalase is more prone to degradation, further depleting the brain’s antioxidant defense and intensifying oxidative stress [8].

AGEs and Amyloid-Beta Interaction

AGEs have significant roles in AD by modifying proteins and interacting with RAGE, which activates inflammatory pathways [48]. AGEs can directly interact with amyloid-β peptides, promoting their aggregation, leading to enhanced plaque formation [49]. This interaction exacerbates neuronal toxicity, triggers glial activation, and increases pro-inflammatory cytokine release. Additionally, AGEs impair protein clearance mechanisms, contributing to amyloid-β accumulation and tau hyperphosphorylation. The combined effects of AGE accumulation, amyloid-β deposition, and oxidative stress accelerates AD progression (Figure 7).

4.3.2. Parkinson’s Disease (PD)

PD, a progressive neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), leading to motor symptoms, such as tremors, rigidity, and bradykinesia [50]. A significant pathological feature of PD is oxidative stress, which arises from excessive ROS production and insufficient antioxidant defenses. Catalase can play an essential role in protecting neurons from oxidative damage [3]. However, in PD, the glycation of catalase disrupts its enzymatic function, exacerbating neuronal degeneration and mitochondrial dysfunction (Figure 8).

4.3.3. Role of CAT Glycation in Dopaminergic Neuron Degeneration

Oxidative Stress in Dopaminergic Neurons

Dopaminergic neurons are particularly susceptible to oxidative stress due to their raised metabolic activity, dopamine oxidation, and their naturally low abundance of antioxidant enzymes, including catalase [51]. Catalase glycation leads to increased ROS accumulation that damages cellular components, accelerating neurodegeneration in patients with PD (Figure 8).

Loss of Antioxidant Defense

Glycation modifies the catalase structure, altering its active site and reducing its enzymatic efficiency. As a result, ROS accumulation disrupts cellular membranes through lipid peroxidation. Moreover, protein oxidation leads to the aggregation of key neuronal proteins, including α-synuclein [52]. The aggregation of α-synuclein forms Lewy bodies, a hallmark of PD pathology. Studies suggest that glycated catalase is prone to degradation, further reducing the neuron’s ability to counteract oxidative damage (Figure 8).

Contribution of AGEs and RAGE Interaction to Neuroinflammation

As a result of excessive protein glycation in patients with PD, formed AGEs interact with RAGE, triggering chronic inflammation and NF-κB activation. The modification of catalase through glycation facilitates this cycle by failing to counteract oxidative stress, thereby amplifying neuronal damage. Neuroinflammation, driven by microglial activation, further accelerates dopaminergic neuron loss in patients with PD (Figure 8).

Impact of Catalase Glycation on Mitochondrial Dysfunction

Mitochondria generate ATP and also produce ROS as byproducts. Glycated catalase cannot remove excess ROS, which damages mitochondrial DNA (mtDNA), leading to defective electron transport chain (ETC) function (Figure 8). Complex I inhibition is a hallmark of PD-related mitochondrial dysfunction [53]. ROS damage from glycated catalase accelerates electron leakage, which decreases energy production, contributing to dopaminergic neuron energy failure and apoptosis. Neurons attempt to clear damaged mitochondria via mitophagy. An increase in AGEs impairs PINK1/Parkin-mediated mitophagy, leading to the accumulation of dysfunctional mitochondria, resulting in energy failure that triggers neuronal apoptosis, worsening PD pathology [54].

5. Preventive Strategies to Counteract Catalase Glycation

5.1. Antioxidant Therapies

Preventing catalase glycation can help to maintain its enzymatic function, thereby reducing ROS accumulation, oxidative damage, and disease progression. Antioxidant therapies, including the use of natural compounds, synthetic agents, and dietary interventions, have been suggested for their potential to protect catalase from glycation and preserve the redox balance (Figure 9) [55].

5.2. The Use of Natural and Synthetic Antioxidants in Preventing Catalase Glycation

Flavonoids play a crucial role in counteracting oxidative stress and glycation-related damage [56]. Quercetin, resveratrol, and catechins act as powerful free radical scavengers, neutralizing ROS that can inhibit AGE formation, reducing glycation-induced structural modifications in catalase. Additionally, flavonoids enhance Nrf2 activation, boosting the expression of catalase and other antioxidant enzymes [57]. By stabilizing catalase and preventing its glycation, flavonoids preserve the cellular redox balance and protect against metabolic and neurodegenerative diseases.

5.2.1. Carotenoids (Beta-Carotene, Lycopene, Astaxanthin)

Carotenoids, including beta-carotene, lycopene, and astaxanthin, act as potent antioxidants that decrease lipid peroxidation [58]. By neutralizing ROS, they help in maintaining cellular integrity and preventing oxidative damage. These compounds can maintain the structural integrity of catalase by preserving its protein structure and preventing glycation-induced modifications that impair its enzymatic activity. Carotenoids further support antioxidant defenses by activating the Nrf2 pathway, enhancing catalase expression [59]. Lycopene protects against metabolic stress, beta-carotene aids neural health, and astaxanthin provides neuroprotection [60]. Through these mechanisms, carotenoids help mitigate oxidative damage, maintain catalase function, and reduce the risk of metabolic and neurodegenerative diseases.

5.2.2. Sulfur-Containing Compounds (Sulforaphane, Allicin from Garlic)

Sulfur-containing compounds, such as sulforaphane, found in cruciferous vegetables, and allicin, derived from garlic, play a crucial role in enhancing antioxidant defenses [61]. These compounds activate the Nrf2 signaling pathway, a key regulator of cellular detoxification and redox homeostasis. Through Nrf2 activation, they upregulate catalase expression, increasing the enzyme’s ability to neutralize hydrogen peroxide and reduce oxidative stress. This enhanced detoxification capacity protects cells from glycation-induced damage and maintains protein integrity. Additionally, sulforaphane and allicin exhibit anti-inflammatory properties, reducing chronic oxidative stress linked to metabolic and neurodegenerative diseases, making them valuable for long-term health and disease prevention.

5.2.3. N-Acetylcysteine (NAC)

NAC boosts glutathione (GSH) production, a key antioxidant that neutralizes ROS and alleviates the oxidative burden [62]. By maintaining the redox balance, NAC can indirectly protect catalase from glycation-induced inactivation, preserving its enzymatic function [63]. This helps prevent protein damage, supports cellular detoxification, and mitigates oxidative stress in patients with metabolic and neurodegenerative diseases.

5.2.4. Aminoguanidine

Aminoguanidine inhibits the formation of AGEs by preventing the interaction between reducing sugars and proteins [64]. This reduces glycation-induced structural modifications in catalase, preserving its enzymatic activity. By lowering glycation stress, aminoguanidine and its nanoformulation maintain antioxidant defenses, mitigating oxidative damage associated with metabolic and neurodegenerative disorders [65].

5.2.5. Metformin

Metformin is a widely used antidiabetic drug, which lowers blood glucose levels while also inhibiting glycation reactions, reducing the formation of AGEs [66]. Additionally, it enhances mitochondrial function, decreases oxidative stress, and activates the AMPK pathway, which protects cells from glycation-induced oxidative damage [67]. Metformin can alleviate cardiac fibrosis and pulmonary congestion by modulating TGF-β, collagen metabolism, and HSP90, providing new insights into potential therapies [68].

5.3. The Role of Vitamins (C, E) and Polyphenols in Catalase Protection

5.3.1. Vitamin C

Vitamin C is a powerful water-soluble antioxidant that can protect catalase from oxidative damage by neutralizing free radicals before they can modify its structure. Vitamin C can inhibit protein glycation reactions, thereby preventing the formation of AGEs [69]. Additionally, vitamin C, along with vitamin E and glutathione, can maintain enzyme integrity and enhance overall cellular defenses [70]. By reducing oxidative stress and glycation, vitamin C can help in preserving catalase activity, supporting metabolic and neuroprotective functions in patients with conditions linked to oxidative damage.

5.3.2. Vitamin E

Vitamin E is a potent lipid-soluble antioxidant that can protect the cell membrane and proteins, including catalase, from oxidative damage [71]. By preventing fatty acid peroxidation, vitamin E helps to maintain cellular integrity and alleviates the oxidative burden, which is crucial in patients with metabolic and neurodegenerative diseases. Additionally, it can play a role in inhibiting glycation-induced modifications of catalase, ensuring its ability to neutralize hydrogen peroxide [55]. By stabilizing antioxidant defenses and reducing oxidative damage, vitamin E contributes to maintaining redox homeostasis, preventing protein dysfunction, and supporting overall cellular health in patients with oxidative stress-related conditions.

5.4. Polyphenols (Curcumin, Epigallocatechin Gallate (EGCG), Resveratrol, Quercetin)

Polyphenols, such as curcumin, EGCG, resveratrol, and quercetin, can exhibit strong antioxidant and antiglycation properties [72]. They can neutralize ROS, inhibit AGE formation, and maintain the structural integrity of catalase function. By activating the Nrf2 pathway, they enhance antioxidant enzyme expression, reducing oxidative stress and protecting against metabolic and neurodegenerative diseases linked to protein glycation [73].

5.4.1. Curcumin

Curcumin exerts a dual antiglycation effect by both limiting the formation of advanced glycation end products (AGEs) and attenuating downstream RAGE-mediated inflammatory and oxidative signaling [74]. By simultaneously reducing carbonyl stress and dampening AGE–RAGE pathway activation (including NF-κB driven cytokine expression and ROS amplification), curcumin preserves the redox balance and mitigates tissue injury. The subsequent sections detail its effects on mitochondrial function, insulin signaling, and neuroinflammatory cascades [75].

5.4.2. Epigallocatechin Gallate (EGCG)

EGCG is a major polyphenol found in green tea that exerts powerful antioxidant effects, benefiting both mitochondrial function and cellular defense systems [76]. It enhances mitochondrial efficiency by reducing oxidative stress and improving energy metabolism, thereby supporting neuronal and metabolic health [77]. EGCG also helps in preserving catalase and SOD, protecting them from oxidative damage and glycation. Additionally, EGCG inhibits the formation of AGEs, reducing the enzyme’s modification and dysfunction [78]. Through these combined actions, EGCG supports redox homeostasis and prevents the cellular damage associated with aging, metabolic disorders, and neurodegeneration.

5.4.3. Resveratrol

Resveratrol, a natural polyphenol found in grapes and berries, possesses strong antioxidant and anti-aging properties [79]. It activates SIRT1, a NAD⁺-dependent deacetylase that plays a key role in cellular stress resistance and metabolic regulation [80]. Through SIRT1 activation, resveratrol enhances the stability and activity of catalase [80]. This effect strengthens the overall antioxidant response, protecting cells from damage caused by ROS and glycation. By maintaining catalase function and improving cellular resilience, resveratrol contributes to the prevention of oxidative damage in patients with metabolic and neurodegenerative disorders.

5.4.4. Quercetin

Quercetin exhibits strong antioxidant and metal chelating properties [81]. It binds to transition metal ions, such as iron and copper, resulting in the production of highly reactive hydroxyl radicals through Fenton reactions. By chelating these metal ions, quercetin prevents excessive ROS generation, thereby reducing oxidative stress and subsequent protein modifications, including glycation [82]. This protective effect helps in preserving the structural integrity and function of catalase. In doing so, quercetin supports the cellular redox balance and has a beneficial role in preventing oxidative damage in patients with chronic metabolic and neurodegenerative conditions. Quercetin has proven neuroprotective effects against ferroptosis in hippocampal neurons through KEAP1 binding and the subsequent activation of the Nrf2/HO-1 pathway [83].

6. Targeting RAGE Signaling and Catalase Stabilization

Emerging therapeutic strategies targeting catalase glycation are gaining translational significance. In particular, RAGE has been identified as a central mediator linking glycation to downstream oxidative and inflammatory cascades. The binding of AGEs to RAGE activates signaling pathways such as MAPK/ERK, JNK, and NF-κB, which amplify ROS generation, upregulate pro-inflammatory cytokines (e.g., TNF-α, IL-6), and perpetuate mitochondrial dysfunction [48]. Pharmacological inhibitors of RAGE, including FPS-ZM1 (a potent small-molecule antagonist of the RAGE–ligand interaction), azeliragon (TTP488, an oral inhibitor tested on patients with Alzheimer’s disease), and soluble RAGE (sRAGE, a decoy receptor that neutralizes circulating AGEs), have shown efficacy in attenuating the oxidative burden and slowing pathological progression in both preclinical and clinical studies [84]. Complementing these upstream approaches, Glorieux and colleagues demonstrated that preserving catalase activity through the stabilization of its heme group, the prevention of glycation at lysine/arginine residues, and the protection of NADPH binding sites, significantly enhances the resistance to oxidative stress [26]. Their findings further suggest that modulating catalase activity can restore redox homeostasis and limit AGE-mediated cellular injury, providing a proof of concept for catalase-directed therapies. Experimental strategies under exploration include enzyme stabilizers, antioxidant cofactors, gene therapy, and engineered catalase variants with improved structural resilience. Together, these approaches demonstrate how interventions can be designed both upstream by blocking RAGE-driven redox–inflammatory signaling and directly at the enzymatic level by safeguarding catalase’s structural integrity and function. Integrating such strategies highlights the clinical relevance of catalase glycation and positions it as a molecular target for improving outcomes in patients with chronic metabolic and neurodegenerative diseases.

7. Conclusions

Catalase glycation represents a significant molecular event that contributes to the progression of oxidative stress-associated diseases, particularly metabolic and neurodegenerative disorders. The non-enzymatic modification of catalase by reducing sugars and reactive carbonyl species leads to structural alterations and enzymatic inactivation, compromising the cell’s ability to detoxify hydrogen peroxide. As a result, ROS accumulate, promoting lipid peroxidation, mitochondrial dysfunction, protein aggregation, and chronic inflammation. In patients with metabolic diseases like diabetes, catalase glycation aggravates β-cell dysfunction, insulin resistance, and end-organ damage. In patients with neurodegenerative conditions, such as Alzheimer’s and Parkinson’s, glycated catalase accelerates neuronal degeneration and impairs mitochondrial homeostasis, leading to cognitive and motor decline. The evidence underscores catalase as both a marker and a mediator of oxidative stress-related cellular dysfunction. Its vulnerability to glycation highlights the need for targeted strategies to preserve its structure and function. Preventive approaches, including antioxidant therapies, antiglycation agents, and the modulation of signaling pathways like Nrf2 and SIRT1, show potential in mitigating glycation-induced damage. Additionally, dietary and pharmacological interventions that preserve catalase integrity can significantly influence disease outcomes. Overall, targeting catalase glycation offers a promising strategy to reduce the oxidative burden, maintain the redox balance, and prevent the progression of chronic metabolic and neurodegenerative diseases.

8. Future Directions

Future research on catalase glycation should prioritize the development of targeted therapeutic strategies that prevent or reverse glycation-induced modifications. A promising direction involves the molecular engineering of catalase to enhance its glycation resistance, such as modifying glycation-prone residues or enhancing protein stability through structural optimization. Furthermore, the identification and design of potent antiglycation compounds with high bioavailability and specificity are essential for effective clinical applications. Another critical avenue is the advancement of drug delivery systems, such as nanoparticle-based carriers, to improve the targeted delivery of catalase-protective agents to oxidative stress-prone tissues like the pancreas, brain, and cardiovascular system. Exploring gene therapy approaches to upregulate catalase expression or correct glycation-damaged enzymes may also offer long-term benefits. In parallel, research should expand into personalized medicine, examining individual susceptibility to catalase glycation and oxidative damage based on genetic and metabolic profiles. This could lead to precision interventions in high-risk populations. Additionally, more studies are needed to understand the interaction between glycated catalase and cellular signaling networks, including the AGE–RAGE axis, and their role in chronic inflammation and disease progression. Integrating these insights with clinical trials will pave the way for innovative therapies aimed at preserving catalase function and improving outcomes in patients with oxidative stress-driven diseases. Taken together, these insights underscore catalase glycation not only as a mechanistic link between metabolic and neurodegenerative disorders, but also as a promising translational target for the development of novel therapeutic strategies aimed at improving clinical outcomes.