Table 1. Characteristics and Main Findings of the Included Studies

No.	Title	Authors and Year	Country	Study Type	Population/Model	Oxidative Stress (OS) Biomarkers or Mechanism Evaluated	Main Findings	Periodontal Implications
1	Periodontitis is an inflammatory disease of oxidative stress: We should treat it that way.	Sczepanik et al., 2020	Brazil	Review	General adult population	Oxidative damage to proteins and DNA; respiratory burst of PMNs.	OS underlies the pathogenesis of several chronic diseases associated with periodontal disease (PD), such as smoking and diabetes.	PD should be treated as an OS-related disease, involving the use of natural antioxidants.
2	Role of Oxidative Stress in Periodontal Diseases.	Patil RT et al., 2024	India	Review	Global periodontal health burden	Mechanisms of reactive oxygen species (ROS) generation; DNA damage.	OS triggers harmful reactions, exacerbating inflammation and bone resorption.	OS weakens antioxidant defenses and increases periodontal destruction.
3	Heme oxygenase-1: potential therapeutic targets for periodontitis.	Lv et al., 2024	China	Review	Global population with PD	Heme oxygenase-1 (HO-1), CO, Fe²⁺.	HO-1 exerts antioxidant and anti-inflammatory activities through heme degradation.	HO-1 induction reduces periodontal tissue destruction.
4	Mechanisms and therapeutic perspectives of mitochondrial dysfunction of macrophages in periodontitis.	Jia et al., 2025	China	Review	Macrophages in periodontitis	Mitochondrial ROS (mtROS), mitochondrial fission.	Increased mitochondrial fission produces excessive mtROS formation in macrophages.	Mitochondrial dysfunction in macrophages contributes to bone and tissue destruction.
5	Interactions Between Neutrophils and Periodontal Pathogens in Late-Onset Periodontitis.	Jiang et al., 2021	China	Review	Neutrophils in PD	Respiratory burst in neutrophils.	Hyperactive neutrophils release massive amounts of ROS in response to bacteria.	ROS have a dual effect, as they may aggravate periodontal inflammation through OS.
6	Effects of Hypoxic Environment on Periodontal Tissue through the ROS/TXNIP/NLRP3 Inflammasome Pathway.	Zhu et al., 2022	China	Experimental (in vivo and in vitro)	Rats and periodontal ligament cells	ROS/TXNIP/NLRP3 inflammasome signaling pathway.	Hypoxia induces excessive ROS production, activating the NLRP3 inflammasome and increasing IL-1β.	Hypoxia-induced OS is a key mechanism linking a hypoxic environment to PD.
7	Diabetes mellitus promotes susceptibility to periodontitis—novel insight into the molecular mechanisms.	Zhao et al., 2023	China	Review	Diabetes mellitus models	AGE/RAGE, ROS, DNA damage.	Hyperglycemia amplifies OS by stimulating ROS production through advanced glycation end products (AGEs).	Prolonged OS damages telomeres in periodontal stem cells, impairing tissue repair.
8	Pathogenic Mechanisms That May Link Periodontal Disease and Type 2 Diabetes Mellitus—The Role of Oxidative Stress.	Mirnic et al., 2024	Serbia	Literature review	Patients with PD and T2DM	OS–inflammation interaction, 8-OHdG.	A synergistic interaction exists in which periodontal infection impairs glycemic control through OS.	Periodontal treatment reduces systemic OS markers, improving the metabolic status of diabetic patients.
9	The Role of Oxidative Stress in the Relationship Between Periodontitis and Alzheimer’s Disease: A Review of the Literature.	Papadakis et al., 2025	Greece	Review	Animal and human models	Cerebral oxidative damage (MDA, 8-OHdG), systemic advanced oxidation protein products (AOPPs).	PD exacerbates cerebral oxidative damage and neuroinflammation, contributing to cognitive decline in Alzheimer’s disease.	Improving periodontal health reduces systemic oxidative burden and the risk of neurodegeneration.
10	Meta-Analysis of Assessment of Total Oxidative Stress and Total Antioxidant Capacity in Patients with Periodontitis.	Mohideen et al., 2023	India	Systematic review and meta-analysis	Patients with PD and healthy controls	Total oxidative status (TOS) and total antioxidant capacity (TAC).	Patients with PD show significantly elevated TOS levels and reduced TAC levels in serum, saliva, and gingival crevicular fluid (GCF).	Redox imbalance is a useful biomarker for assessing PD progression and therapeutic efficacy.
11	Hyperglycemia Aggravates Periodontitis via Autophagy Impairment and ROS-Inflammasome-Mediated Macrophage Pyroptosis.	Zhao et al., 2023	China	Experimental (in vivo and in vitro)	Rats and macrophages	Macrophages, ROS, inflammasome-mediated pyroptosis.	Hyperglycemia impairs macrophage autophagy, exacerbating ROS production and pyroptosis.	Systemic OS caused by diabetes accelerates inflammatory aging in periodontal tissues.
12	The Effect of Melatonin on Periodontitis.	Konečná et al., 2021	Slovakia	Experimental (animal and clinical)	Rats and patients with PD	AGEs, advanced oxidation protein products (AOPPs), TAC.	Melatonin reduces bone loss and improves OS levels in saliva in animal models.	In humans, melatonin treatment did not show significant short-term clinical changes (2 weeks), suggesting the need for longer studies.
13	Oxidative Stress and FOXO-1 Relationship in Stage III Periodontitis.	Gurbuz et al., 2024	Turkey	Cross-sectional observational	Patients with Stage III periodontitis, Grades B and C	8-OHdG (DNA damage), transcription factor FOXO1.	8-OHdG levels are elevated and FOXO1 levels are reduced in the saliva of patients with advanced periodontitis.	Low FOXO1 expression, which is important for antioxidant enzymes, promotes tissue destruction in PD.
14	Patent Mining on the Use of Antioxidant Phytochemicals in the Technological Development for the Prevention and Treatment of Periodontitis.	Jos et al., 2024	Brazil	Review	Dental technological development	Free-radical neutralization, KEAP1-NRF2 pathway.	Growing interest in patents involving phytochemicals (vitamin C, quercetin, etc.) to neutralize OS in PD.	Adjunctive antioxidant therapies applied in gels or dentifrices improve the clinical response to conventional treatment.
15	Targeting Nrf2 with Probiotics and Postbiotics in the Treatment of Periodontitis.	Karaca et al., 2022	Finland	Literature review	Patients with suppressed immune responses	Nrf2 activation, cytotoxic respiratory burst.	Probiotics and postbiotics may activate antioxidant mechanisms through Nrf2 to suppress excessive OS.	Restoring impaired Nrf2 responses is a promising strategy for high-risk or treatment-resistant patients.
16	Modern views on the etiology and role of microbial persistence in the development of inflammatory processes in the periodontal complex (review).	Marfiian et al., 2024	Ukraine	Review	Periodontal complex	Free-radical oxidation, lipid and protein peroxidation.	OS and impairment of the antioxidant system are key pathogenic links that remain insufficiently studied.	Microbial persistence dysregulates local and systemic oxidative balance in generalized PD.
17	Salivary Redox Homeostasis in Human Health and Disease.	Cižmárová et al., 2022	Slovakia	Review	Human health and disease	MDA, 8-OHdG, SOD enzymes.	Saliva reflects local redox imbalance: increased MDA and 8-OHdG in patients with chronic periodontitis.	Periodontal treatment does not always significantly or immediately improve salivary OS levels.
18	Avoiding implant-related complications in medically compromised patients with or without unhealthy lifestyle / Elevated oxidative stress.	Guabello et al., 2023	Italy	Review	Systemically compromised patients, with or without harmful habits	ROS generated by friction and corrosion.	Implant placement inevitably generates ROS due to disruption of the titanium oxide layer.	Elevated OS in systemically compromised patients increases the risk of peri-implant complications.
19	Effect of Hesperidin on Barrier Function and Reactive Oxygen Species Production in an Oral Epithelial Cell Model, and on Secretion of Macrophage-Derived Inflammatory Mediators during Porphyromonas gingivalis Infection.	Maquera et al., 2023	Canada	Experimental (in vitro)	Oral epithelial cells and macrophages	ROS production by P. gingivalis, NF-κB activation.	Hesperidin reduces ROS production in stimulated epithelial cells and attenuates the secretion of pro-inflammatory cytokines.	The flavonoid hesperidin may act as an adjunctive agent by protecting the epithelial barrier against oxidative damage.
20	Reactive oxygen species can be traced locally and systemically in apical periodontitis: A systematic review.	Georgiou et al., 2021	Netherlands	Systematic review	Patients with apical periodontitis (AP)	MDA expression, serum antioxidants.	AP induces local ROS production and increases systemic OS in blood and saliva.	Nitric oxide plays a fundamental role in periapical bone resorption and lesion progression.
21	Research efficacy of gaseous ozone therapy as an adjuvant to periodontal treatment on oxidative stress mediators in patients with type 2 diabetes: a randomized clinical trial.	Rapone et al., 2023	Italy	Randomized clinical trial	Diabetic patients with moderate or severe PD	TOS, TAS, GSH, plasma MDA.	Gaseous ozone treatment as an adjunct to mechanical therapy improved clinical parameters but did not significantly improve plasma OS markers.	Although ozone is theoretically a potent antioxidant, clinical evidence still requires further standardized research in diabetic patients.
22	Influence of Reactive Oxygen Species on Wound Healing and Tissue Regeneration in Periodontal and Peri-Implant Tissues in Diabetic Patients.	Buranasin et al., 2023	Thailand	Review	Diabetic patients with PD	ROS-induced insulin resistance, Akt activation.	Excess ROS damages proteoglycans and collagen, impairing healing in diabetic patients.	Antioxidants may improve tissue regeneration impaired by hyperglycemic conditions.
23	Ferroptosis: A New Development Trend in Periodontitis.	Chen et al., 2023	China	Review	Basic medical research	Ferroptosis, iron overload, lipid peroxidation (MDA).	The development of PD is accompanied by iron overload and glutathione (GSH) depletion, suggesting the presence of ferroptosis.	Ferroptosis acts as a novel mechanism of oxidative cell death and tissue damage in the periodontium.
24	Mitochondrial function in oral health and disease.	Ramos et al., 2022	United States	Review	Mitochondrial proteomics and metabolomics	Dysfunction of oxidative phosphorylation (OXPHOS).	PD is an inflammatory disease of the attachment apparatus associated with excessive ROS production.	Periodontal health strongly depends on mitochondrial homeostasis in host cells.
25	The role of Mitofusin-1 and Mitofusin-2 in periodontal disease: a comprehensive review.	Varma et al., 2025	United Arab Emirates	Review	Periodontal tissue homeostasis	Mitochondrial integrity, MFN1 and MFN2, mitochondrial fusion.	Reduced MFN1 and MFN2 levels correlate with increased OS, inflammation, and mitochondrial fragmentation.	Targeting mitofusins therapeutically may improve regeneration and management of PD.
26	Mitochondrial Dysfunction in the Pathogenesis and Treatment of Oral Inflammatory Diseases.	Dong et al., 2023	China	Review	Oral inflammatory diseases	Mitochondrial membrane potential, OPA1 cleavage, mtROS.	Mitochondrial dysfunction contributes to PD by affecting OS and regulating the inflammatory response.	Strategies aimed at restoring mitochondrial function reduce osteoblast apoptosis.
27	Ferroptosis and cuproptosis in periodontitis: recent biological insights and therapeutic advances.	Zheng et al., 2025	China	Systematic review	Synthesis of findings	Ferroptosis and cuproptosis, GSH pathway, copper/iron imbalance.	Pathogen-driven metal homeostasis imbalance increases periodontal OS.	OS is a unifying mechanism linking ferroptosis and cuproptosis in periodontal destruction.
28	Molecular hydrogen: Mechanism against oxidative stress and application in periodontitis: A review.	Ying et al., 2025	China	Literature review	Periodontal treatment	Selective scavenging of hydroxyl radicals and peroxynitrite; Nrf2 pathway.	Molecular hydrogen acts as a potent antioxidant by reducing excessive ROS levels.	Its application before, during, and after periodontal surgery helps restore redox balance.
29	Hyperhomocysteinaemia aggravates periodontitis by suppressing the Nrf2/HO-1 signalling pathway.	Yang et al., 2025	China	Literature review	Periodontal and systemic health	Nrf2 pathway, 8-OHdG levels, ROS.	Hyperhomocysteinemia inhibits Nrf2 translocation, increasing oxidative damage (8-OHdG).	Elevated homocysteine levels act as a contributing factor to periodontal bone loss through OS.
30	The Periodontal–Cardiovascular Disease Association: Molecular Mechanisms and Clinical Implications.	Ferrara et al., 2025	Italy	Review	Patients with PD and cardiac risk	NOX2 activation, peroxynitrite, NO bioavailability.	NOX2-mediated OS increases superoxide production, reducing NO and causing endothelial dysfunction.	The molecular link between PD and cardiovascular disease is based on the systemic propagation of oxidative and pro-inflammatory mediators.
31	Hypochlorous acid solution serves as a potential anti-biofilm therapy for periodontitis via targeting quorum sensing of periodontal pathogens.	Lv et al., 2025	China	Experimental (in vitro and in vivo)	Periodontal biofilm	Hypochlorous acid (HOCl), bacterial oxidative stress.	The imbalance between bacterial plaque and host defense generates toxic products and OS.	Bacterial resistance to OS perpetuates periodontal infection.

Source: own elaboration.

LITERATURE REVIEW

Periodontal Diseases and Oral Microbiota:

Periodontal disease (PD) affects 10% to 15% of the population¹,³, although up to 90% of individuals have experienced some manifestation of the disease⁸,¹⁴. It is characterized by chronic inflammation and progressive destruction of the tooth-supporting tissues, and its primary etiology is associated with microorganisms present in dental plaque; however, its progression and severity depend on the host's immunoinflammatory response¹⁵–¹⁸.

The accumulation of dysbiotic biofilms, with a predominance of pathogens belonging to the “red complex” (Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola) and Aggregatibacter actinomycetemcomitans, initiates the process¹⁶,¹⁹. However, tissue destruction results from the host response and the underlying redox imbalance. Therefore, PD is a dysbiotic condition in which the microbial community becomes imbalanced and potentiates inflammation²,⁵,¹⁴.

Oxidative Stress and Reactive Oxygen Species:

Free radicals are chemical species with unpaired electrons that participate in metabolic processes, cellular signaling, and defense responses when maintained at controlled levels⁸,¹⁷,²⁰,²¹. However, their high reactivity represents a risk to cellular integrity if their production is not adequately regulated⁸. To counteract their harmful effects, cells possess antioxidant systems that preserve redox balance, the dynamic equilibrium between free radicals and the body's capacity to neutralize them²,¹⁷, thereby preventing or delaying structural and functional damage to essential biomolecules²,¹⁷.

OS occurs when there is an imbalance between the production of oxidizing agents and antioxidant capacity⁹,¹⁷,¹⁸, a situation in which regulatory mechanisms become insufficient to maintain homeostasis due to excessive free radical production⁸,¹⁷,²⁰. Consequently, cellular damage is triggered through the oxidation of lipids, proteins, and nucleic acids, altering cellular function and promoting the development of pathological processes⁸. Therefore, OS has been implicated in various chronic diseases, including periodontitis¹⁶,¹⁷,²⁰.

Reactive Oxygen Species:

Exogenous and Endogenous Sources:

ROS are highly reactive by-products of aerobic metabolism, originating from approximately 5% of the oxygen consumed by cells². They may originate from exogenous sources (radiation, cigarette smoke, intense exercise, and tissue injury) or endogenous sources (by-products of metabolic pathways, immune cell activity, and connective tissue processes)²,¹⁷,¹⁸. When their production exceeds cellular regulation, they become central mediators of oxidative imbalance and inflammatory tissue damage¹,¹³,¹⁷,²².

ROS Production in Periodontal Disease:

Neutrophils:

Polymorphonuclear neutrophils (PMNs) are the primary source of ROS in PD¹,²,¹⁵,²³, accounting for 50% to 60% of immune cells in the gingival sulcus and periodontal tissues under inflammatory conditions¹,²,⁵,²². Although they maintain homeostasis under healthy conditions, bacterial stimulation induces a hyperactive phenotype⁵. This bactericidal increase in ROS generates a collateral cytotoxic effect that promotes tissue deterioration and bone loss¹,⁵,¹²,¹⁴,²².

Respiratory Burst:

PMNs and macrophages generate massive amounts of ROS through the respiratory burst, a process dependent on the NADPH oxidase enzyme complex⁵,⁸. Its excessive or prolonged activation extends oxidative damage to the surrounding periodontal tissues⁵.

Mitochondrial ROS Production:

Aerobic Metabolism:

During oxidative phosphorylation, electron leakage reduces O₂ to the superoxide anion (O₂⁻), which subsequently gives rise to hydrogen peroxide (H₂O₂) and the hydroxyl radical (·OH)²,¹¹,²⁴.

Mitochondrial Dysfunction:

Alteration of quality-control mechanisms such as mitophagy, which is common under conditions of hyperglycemia, prevents the elimination of damaged mitochondria, resulting in sustained elevation of ROS¹¹,²⁴–²⁶. This is compounded by local hypoxia, infection with P. gingivalis⁶,¹⁹, and ferroptosis, which depletes antioxidant capacity and intensifies the inflammatory process²³,²⁷.

Oxidative Stress in Periodontal Disease:

OS acts as a link between the inflammatory response and tissue destruction¹³,²². In periodontitis, an increase in local ROS is observed together with depletion of antioxidant systems³,¹⁰,¹⁷,²², establishing OS as a key etiopathogenic factor in this disease¹,²,¹⁸ (Table 2).

Molecular Mechanisms of Periodontal Damage:

Excessively generated ROS trigger harmful reactions that affect fundamental biological components, compromising the structural and functional integrity of periodontal tissues²,³,¹⁷:

Lipid Peroxidation (LPO):

The attack on polyunsaturated fatty acids in cell membranes produces lipid hydroperoxides and reactive aldehydes, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). In addition, LPO promotes the production of prostaglandin E₂ (PGE₂), a mediator involved in bone resorption, thereby contributing to alveolar bone loss in periodontitis²,³.

Protein Damage:

Oxidation of carbon double bonds and side chains induces the formation of protein carbonyls, altering essential cellular processes such as migration, proliferation, and maintenance of periodontal tissues¹,²,¹⁸,²².

DNA Damage:

Radicals such as ·OH and peroxynitrite induce strand breaks and the formation of 8-hydroxy-2′-deoxyguanosine (8-OHdG)². These genetic lesions may result in insertions, deletions, sequence amplification, and DNA strand breaks, affecting genomic stability and cellular viability in periodontal tissues²,³,¹⁷.

Role of Oxidative Stress in the Progression of Periodontal Disease:

Alteration of Periodontal Cell Function:

OS directly compromises cellular physiology by inhibiting the migration and proliferation of gingival fibroblasts and periodontal ligament cells, which are essential for tissue maintenance and repair¹³,¹⁸,²⁶. Furthermore, ROS overproduction induces apoptosis in these cells, limiting the regenerative capacity of the periodontium and accelerating the progressive degradation of the extracellular matrix²,²².

Amplification of the Inflammatory Response:

ROS modulate the inflammatory response by activating redox-sensitive transcription factors, such as nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs)²,²⁸. This signaling triggers the massive release of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α)²–⁴,⁸, which, in turn, stimulates further ROS production by immune cells, establishing a self-sustaining interaction between inflammation and oxidative damage².

Imbalance in Bone Remodeling:

At the bone level, OS alters the regulatory RANKL/osteoprotegerin (OPG) axis¹,¹⁴. RANKL overexpression stimulates osteoclast differentiation and activation, while oxidative damage induces dysfunction and apoptosis of osteoblasts⁵,⁷. As a result, an imbalance favoring alveolar bone resorption occurs, accelerating the bone loss characteristic of PD³,⁴,⁷,²².

Perpetuation of Tissue Damage:

A persistent oxidative microenvironment promotes the activation of matrix metalloproteinases (MMP-8 and MMP-9), enzymes responsible for degrading collagen and the extracellular matrix of the attachment apparatus¹,³,⁴,²⁰. The sustained activity of these proteases contributes to progressive tissue destruction and perpetuates the progression of PD²⁰,²⁹.

Table 2: Biomarkers of oxidative damage in periodontal disease.

Marker	Type of Damage	Finding in PD	Periodontal Implication
Reactive oxygen species (ROS)	General process of OS and cellular signaling¹,².	Massive overproduction, mainly by hyperactive PMNs²,⁵.	Direct damage to macromolecules²,⁸. Enhancement of bone resorption²,⁷,²².
Malondialdehyde (MDA)	Lipid peroxidation (LPO)².	Significantly elevated levels in saliva, gingival crevicular fluid (GCF), and serum³,¹⁴,³⁰.	Positive correlation with probing depth and severity of periodontal destruction²,¹²,¹⁸.
Protein carbonyls	Oxidative damage to proteins¹,¹⁸,²².	Significantly higher levels in patients with PD¹,²²,³⁰.	Positive correlation with advanced clinical attachment loss and collagen degradation¹,²².
8-OHdG	Oxidative DNA damage².	Increased levels in saliva and GCF of patients with periodontitis³,⁷,²².	Promotes apoptosis of osteoblasts and fibroblasts³,¹³,³⁰. Positive correlation with disease severity³,¹³,¹⁸,²².
Total oxidative status (TOS)	Global measure of the total oxidant burden in a given environment¹⁰,²¹.	Significant increase in serum, GCF, and saliva of affected patients¹⁰,²¹.	Reflects the magnitude of local and systemic oxidative burden and the status of disease activity¹,¹⁰.
Total antioxidant capacity (TAC)	Status of total antioxidant defenses¹⁰,¹⁸,²¹.	Decreased levels in saliva, GCF, and serum, indicating depletion of the defense system³,¹⁰,²¹,²².	An imbalance favoring oxidation predisposes to progressive degradation of supporting tissues¹⁰,²².

Source: own elaboration.

Systemic Factors Associated with Oxidative Stress:

Various systemic conditions exacerbate oxidative stress (OS) and promote the progression of periodontitis by intensifying the host's inflammatory and oxidative response¹,¹⁰,²⁶,³⁰. This interaction highlights the bidirectional nature of periodontitis with multiple systemic diseases²⁷. The main mechanisms involved in this interaction are summarized in Table 3.

Diabetes Mellitus:

Diabetes mellitus, a metabolic disorder characterized by persistent hyperglycemia, maintains a close bidirectional relationship with periodontitis and is the sixth most common complication in patients with diabetes¹,⁷,⁸. Chronic hyperglycemia increases ROS production at the periodontal level, promoting osteoblast apoptosis, osteoclast activation, and alveolar bone loss¹,⁷,¹⁸,²². Likewise, the accumulation of advanced glycation end products (AGEs) and their binding to the receptor for advanced glycation end products (RAGE) activates the NF-κB pathway in macrophages and endothelial cells, amplifying the release of ROS and pro-inflammatory cytokines¹,⁸,¹⁸,²². This is accompanied by PMN dysfunction and a hyperinflammatory state that accelerates tissue destruction⁷.

Smoking:

Tobacco consumption exacerbates periodontal OS, increasing the risk and severity of periodontitis¹,¹⁸. Although nicotine causes vasoconstriction, thereby reducing bleeding on probing and masking active inflammation, it promotes a dysfunctional immune response characterized by PMN hyperactivation and ROS overproduction¹. At the bone level, it alters the RANKL/OPG axis by reducing OPG and increasing the RANKL/OPG ratio, thereby stimulating osteoclastogenesis and alveolar bone loss¹,¹⁸. In addition, hydrocarbons in tobacco smoke activate the aryl hydrocarbon receptor, stimulating osteoclastic differentiation, while nicotine increases ROS generation in gingival fibroblasts and decreases local antioxidant capacity in a dose-dependent manner¹,¹⁸.

Hyperhomocysteinemia:

Hyperhomocysteinemia (HHcy), characterized by elevated concentrations of homocysteine in the blood, is associated with endothelial dysfunction, chronic inflammation, and increased OS²⁹.

HHcy promotes OS by increasing ROS accumulation, enhancing the expression of pro-inflammatory mediators, and suppressing the body's antioxidant defenses. In patients with periodontitis and HHcy, greater clinical attachment loss and bone resorption have been observed, accompanied by increased local and systemic inflammation, suggesting a synergistic effect between both conditions²⁹.

This phenomenon is explained, in part, by the fact that elevated homocysteine concentrations inhibit the Nrf2/HO-1 signaling pathway, the principal cellular antioxidant defense mechanism. Alteration of this pathway promotes increased ROS production and osteoclastogenesis in periodontitis²⁸,²⁹

Table 3: Systemic diseases associated with oxidative stress and their periodontal effects.

Systemic Disease	Mechanism Related to OS	Periodontal Effects
Diabetes mellitus	Hyperglycemia with increased ROS¹,⁷,¹⁸,²², activation of NF-κB¹,¹⁸,²², PMN dysfunction, and a persistent state of hyperinflammation⁷.	Intensification of the periodontal inflammatory response, increased osteoblast apoptosis, osteoclast activation, and greater alveolar bone loss⁷,²².
Smoking	Increased total oxidant status induced by components of tobacco smoke¹,¹⁸; ROS overproduction by hyperactivated PMNs; reduction in total antioxidant capacity; alteration of the RANK/RANKL/OPG system¹.	Increased osteoclastogenesis and alveolar bone loss; local immune dysfunction; accelerated progression of periodontal destruction with less clinical expression of inflammation¹,¹⁸.
Hyperhomocysteinemia	Elevated ROS, suppression of antioxidant defenses; inhibition of the Nrf2/HO-1 pathway; endothelial dysfunction and chronic systemic inflammation²⁹.	Greater clinical attachment loss and alveolar bone resorption; increased periodontal tissue damage due to a synergistic effect between OS and inflammation²⁹.

Source: own elaboration.

Therapeutic Strategies Related to Oxidative Stress:

Non-surgical periodontal therapy has demonstrated a positive impact on redox balance, as evidenced by a reduction in oxidative stress (OS) markers and an increase in total antioxidant capacity, confirming that biochemical parameters reflect periodontal status and the response to treatment¹,¹⁰,¹⁷. However, in addition to the conventional approach, various studies³,⁷,¹⁴ have proposed the use of adjunctive therapeutic strategies aimed at modulating OS, including antioxidant supplementation⁷,¹⁴ and the development of emerging therapies¹⁹,²⁸,³¹, which have shown promising results for the treatment of periodontitis.

Antioxidants in Periodontal Therapy:

Pharmacological and natural antioxidants have demonstrated considerable potential as adjunctive therapies in the treatment of periodontitis by counteracting OS and modulating the inflammatory response¹,⁴,²². Drugs such as metformin, in addition to their antihyperglycemic effect, promote gingival healing and angiogenesis³. Similarly, natural compounds such as vitamin C, quercetin, resveratrol, and coenzyme Q10 have demonstrated antioxidant and anti-inflammatory effects in the periodontal context⁴,⁷,¹⁴,²². The main agents evaluated and their clinical evidence are summarized in Table 4.

Table 4: Antioxidants evaluated as adjuncts in periodontal therapy.

Agent	Type	Suggested Use	Mechanism Related to OS	Evidence in PD
Metformin	Pharmacological	Commonly used in type 2 diabetes mellitus³. Its potential cytoprotective effect is under investigation³.	Reduces intracellular levels of free radicals³. Modulation of OS and improvement of tissue response, promoting healing and angiogenesis³.	Improves healing and periodontal parameters³.
Vitamin C	Natural (vitamin)	500–2000 mg/day as an adjunct to scaling and root planing¹⁴,²². Local application in gel⁷.	Potent ROS scavenger and prevents endothelial dysfunction¹⁴. Neutralization of ROS and attenuation of inflammatory pathways¹⁴.	Reduction of periodontal inflammation¹⁴. Improvements in periodontal parameters¹⁴,²².
Quercetin	Natural (flavonoid)	Natural extracts or incorporation into membranes for tissue regeneration¹⁴.	Activation of Nrf2, increasing cellular antioxidant capacity; inhibition of macrophages¹⁴. Stimulates the expression of endogenous antioxidant enzymes¹⁴.	Prevents oxidative damage in periodontal ligament cells¹⁴. Reduces alveolar bone loss (animal models)¹⁴,²⁷.
Resveratrol	Natural (polyphenol)	Oral administration: 500 mg/day (effective high dose)¹⁴.	Nrf2 activation¹,⁴; reduction of pro-inflammatory cytokines¹⁴. Direct action against ROS overproduction¹,⁴.	Improves clinical attachment level, probing depth, and bleeding index¹⁴. Prevents disease progression and bone loss (animal models)¹,²².
Coenzyme Q10 (CoQ10)	Natural (endogenous)	Topical application in gel⁴.	Protects mitochondria, proteins, and DNA against oxidative damage⁴. Reduces inflammation activation induced by OS⁴.	Effective in improving gingival index, probing depth, and clinical attachment level⁴. Inhibits bone loss⁴. CoQ10 levels are reduced in 80% of patients with periodontitis⁴.

Source: Own elaboration.

Emerging Therapies:

Innovative strategies, such as the use of molecular hydrogen²⁸, postbiotics¹⁵, flavonoids¹⁴, nanomaterials¹⁴, and local delivery systems²⁶, represent promising approaches for modulating OS and improving therapeutic efficacy in PD⁴,²². Likewise, some therapies seek to act directly on the biofilm through controlled oxidative mechanisms, offering new alternatives as adjunctive treatments²,¹³,¹⁴. The main emerging strategies aimed at modulating OS are detailed in Table 5.

Table 5. Emerging Strategies Targeting Oxidative Stress in Periodontal Therapy

Strategy	Approach	Suggested Use	Relationship with OS	Periodontal Effects	Status
Molecular hydrogen (H₂)	Selective antioxidant28.	Consumption of hydrogen-rich water28. Mouthwash for disinfection28. Inhalation or local injection28.	Neutralizes ·OH28. Activates Nrf2 and inhibits MAPK and NF-κB pathways28.	Reduces osteoclast differentiation and DNA damage28. Improves probing depth and clinical attachment level28.	Experimental.
Postbiotics	Host modulation15.	Local administration or administration of bacterial metabolites15.	Activation of the Nrf2 pathway15. Reduces intracellular ROS levels15.	Reduces inflammatory burden and oxidative damage15. May prevent recurrence in susceptible patients15.	Experimental.
Flavonoids (hesperidin)	Anti-inflammatory19.	Slow-release gels or oral hygiene products19.	Inhibition of P. gingivalis-mediated ROS production19. Inhibition of the NF-κB pathway19.	Protects the integrity of the gingival epithelial barrier19. Reduces secretion of proinflammatory cytokines and MMPs19.	Preclinical.
Nanomaterials	Local delivery4,26.	Locally administered nanoparticles in periodontal pockets4,26.	Eliminate ROS at sites with elevated OS4,26. Enable greater antioxidant bioavailability4,26.	Improve osteogenic differentiation capacity in stem cells4,26. Restore mitochondrial function and promote tissue repair4,26.	Experimental.
Hypochlorous acid	Controlled oxidant31.	Solution (100 mg/L) for periodontal irrigation.	Targeted production of OS against biofilm31.	Effective biofilm destruction31. Significant reduction in bone resorption and inflammation31. High biocompatibility with host cells31.	Experimental/Adjunctive.

Source: Own elaboration.

DISCUSSION

Overall, the reviewed evidence confirms that oxidative stress (OS) constitutes a relevant component of the pathogenesis of periodontal disease (PD); however, its interpretation varies according to the study approach. Whereas Zhao et al.⁷ and Mirnic et al.8 position OS as a central axis capable of integrating systemic factors, Jia et al.⁴ and Marfiian et al.16 analyze it as a phenomenon secondary to bacterial dysbiosis. The findings of the present analysis indicate that there is no definitive consensus as to whether OS acts as an initiator of tissue damage or as an amplifier of a previously dysregulated inflammatory response.

One of the main discrepancies identified concerns the nature of redox imbalance. Sczepanik et al.¹and Georgiou et al.²⁰raise a fundamental question regarding whether decreased total antioxidant capacity (TAC) in gingival crevicular fluid (GCF) is a cause or a consequence of inflammation. On the one hand, some studies, such as those by Guabello et al.¹⁸ and Patil et al.², argue that OS acts as an active mediator by enhancing proinflammatory cytokines and promoting tissue destruction; on the other hand, Karaca et al.¹⁵ reported that oxidative damage is an inevitable consequence of neutrophil hyperactivity in response to the biofilm. This distinction is critical because it determines whether the therapeutic approach should focus on eliminating the bacterial stimulus or additionally modulating the redox environment.

Regarding biomarkers, although the meta-analysis conducted by Mohideen et al.¹⁰ reported a consistent increase in oxidative damage markers in patients with periodontitis, their diagnostic utility remains limited when different biological matrices are compared. This is attributable to notable discrepancies concerning whether saliva accurately reflects the processes occurring in GCF: whereas Guabello et al.18 and Lv et al.³ found a direct correlation with clinical severity, Papadakis et al.⁹ warned that exposure of the oral cavity to environmental factors, such as tobacco and diet, destabilizes the local redox balance and reduces the diagnostic utility of these biomarkers.

Nevertheless, the measurement of these OS markers cannot currently be recommended for routine clinical practice because of the lack of methodological standardization and defined reference values. Furthermore, a relevant methodological aspect identified in this review is the predominance of narrative and experimental studies, together with the scarcity of clinical trials and longitudinal studies. This distribution indicates that, although the role of OS in PD is broadly supported, its clinical validation and diagnostic applicability still require stronger scientific evidence.

Another factor complicating the interpretation of OS is the adaptive capacity of certain periodontopathogens to oxidative environments. In the review by Jiang et al.5, it was established that species such as P. gingivalis express antioxidant enzymes that neutralize reactive oxygen species (ROS) and promote their survival in an inflammatory environment. This suggests that OS is not merely a consequence of the host response, but also a dynamic component of the interaction with microorganisms that contributes to bacterial persistence and maintenance of the inflammatory process.

On the other hand, an important aspect identified in the literature is the difference in OS levels between systemically healthy patients and those with associated systemic diseases. Studies such as those by Sczepanik et al.¹ and Guabello et al.¹⁸ indicate that conditions such as diabetes mellitus and smoking may intensify the host oxidative state, promoting a more pronounced inflammatory response and greater periodontal destruction. In these patients, increased ROS production has been observed, together with reduced antioxidant defenses, generating a tissue environment that is more susceptible to oxidative damage and disease progression. Similarly, Zhao et al.⁷ and Buranasin et al.²² show that systemically healthy individuals appear to have a more regulated oxidative response, which could explain a slower progression of periodontal damage. This reinforces the concept that OS does not act in isolation but may be significantly modulated by the patient's systemic status.

Regarding PD progression following conventional treatment, sustained activation of pathways such as nuclear factor kappa B (NF-κB) could perpetuate an inflammatory state that is partially independent of the initial bacterial stimulus. A difference in clinical interpretation arises here: some authors, such as Lv et al.3 and Jia et al.⁴, maintain that scaling and root planing is sufficient to restore the local oxidative balance, whereas more recent research, such as that by Zhao et al.¹¹, suggests that in patients with a high oxidative burden or systemic comorbidities, conventional therapy does not always completely restore tissue homeostasis. This could explain why mechanical treatments are unsuccessful at certain sites, as OS may create a microenvironment that favors chronicity and limits inflammatory resolution.

Likewise, a gap persists between experimental evidence and clinical outcomes in the therapeutic field. According to Sczepanik et al.¹, resveratrol has demonstrated potent inhibitory effects on bone damage in animal models; however, clinical trials in humans have yielded inconsistent results, according to Buranasin et al.²². Furthermore, although studies such as that by Jos et al.14 have reported additional benefits from the use of adjunctive antioxidants, others, such as Sczepanik et al.¹, have found no significant advantages from adding supplemental doses of vitamin C to conventional therapy. Consequently, current evidence does not support the routine use of antioxidants as standard therapy in periodontics, although they may be considered adjunctive strategies in specific clinical contexts.

Finally, a potential transition is suggested from an approach focused exclusively on infection control toward a more individualized view of the disease. The current debate is oriented toward understanding each patient's oxidative profile and how it influences disease progression and treatment response. Research into regulatory pathways such as Nrf2/HO-1, as described by Lv et al.³, opens new perspectives for the development of more specific therapeutic strategies. However, the available clinical evidence remains limited for the routine translation of these advances into clinical practice.

Despite the findings described above, the present literature review has certain limitations that should be considered when interpreting its results. First, the search was restricted to articles published exclusively in English within a specific time range (2020–2025), which may have resulted in the omission of relevant evidence published in other languages or seminal studies conducted before this period. In addition, there is considerable heterogeneity in the methodologies used by the included studies, ranging from animal models and in vitro cell cultures to clinical trials with diverse diagnostic criteria for periodontitis and different methods for measuring oxidative stress markers, which makes direct comparison between findings difficult. Finally, the possibility of publication bias must be acknowledged, as studies reporting statistically significant results tend to be published more frequently than those with null or non-significant findings.

CONCLUSIONS

Oxidative stress plays a relevant role in the etiopathogenesis of periodontal disease by contributing to the amplification of the inflammatory response and the progressive destruction of the tooth-supporting tissues. However, current evidence does not allow a clear determination of whether OS acts as an initiating factor in tissue damage or as a consequence of a previously established inflammatory process.

On the other hand, oxidative damage biomarkers are associated with disease severity; however, their diagnostic use is limited by methodological heterogeneity, variability among biological matrices, and the absence of standardized reference values.

Finally, conventional periodontal therapy contributes to improving the local redox balance, but the available evidence does not support the routine use of antioxidants as part of standard treatment. Although they represent a promising alternative in specific contexts, clinical studies are required to establish their actual efficacy and to define their clinical indications more precisely.

REFERENCES

1. Sczepanik FSC, Grossi ML, Casati M, Goldberg M, Glogauer M, Fine N, et al. Periodontitis is an inflammatory disease of oxidative stress: We should treat it that way. Periodontol 2000. 2020;84(1):45-68. https://doi.org/10.1111/prd.12342

2. Patil RT, Dhadse PV, Salian SS, Punse SD. Role of Oxidative Stress in Periodontal Diseases. Cureus. 2024;16(5):e60779. https://doi.org/10.7759/cureus.60779

3. Lv W, Hu S, Yang F, Lin D, Zou H, Zhang W, et al. Heme oxygenase-1: potential therapeutic targets for periodontitis. PeerJ. 2024;12:e18237. https://doi.org/10.7717/peerj.18237

4. Jia Y, Li Z, Huang P, Wang Y, Yang B. Mechanisms and therapeutic perspectives of mitochondrial dysfunction of macrophages in periodontitis. Front Cell Infect Microbiol. 2025;15:1634909. https://doi.org/10.3389/fcimb.2025.1634909

5. Jiang Q, Zhao Y, Shui Y, Zhou X, Cheng L, Ren B, et al. Interactions Between Neutrophils and Periodontal Pathogens in Late-Onset Periodontitis. Front Cell Infect Microbiol. 2021;11:627328. https://doi.org/10.3389/fcimb.2021.627328

6. Zhu R, Mi X, Li Y. Effects of Hypoxic Environment on Periodontal Tissue through the ROS / TXNIP / NLRP3 Inflammasome Pathway. Biomed Res Int. 2022;2022:35083332. https://doi.org/10.1155/2022/35083332

7. Zhao M, Xie Y, Gao W, Li C, Ye Q, Li Y. Diabetes mellitus promotes susceptibility to periodontitis—novel insight into the molecular mechanisms. Front Endocrinol (Lausanne). 2023;14:1192625. https://doi.org/10.3389/fendo.2023.1192625

8. Mirnic J, Djuric M, Brkic S, Gusic I, Stojilkovic M, Tadic A, et al. Pathogenic Mechanisms That May Link Periodontal Disease and Type 2 Diabetes Mellitus—The Role of Oxidative Stress. Int J Mol Sci. 2024;25(18):9806. https://doi.org/10.3390/ijms25189806

9. Papadakis KA, Doufexi AE, Kalamaki MS, Bourazanas E, Lymperaki E. The Role of Oxidative Stress in the Relationship Between Periodontitis and Alzheimer's Disease: A Review of the Literature. J Pers Med. 2025;15(1):40863446. https://doi.org/10.3390/jpm15010000

10. Mohideen K, Chandrasekaran K, Veeraraghavan H, Faizee SH, Dhungel S, Ghosh S. Meta-Analysis of Assessment of Total Oxidative Stress and Total Antioxidant Capacity in Patients with Periodontitis. Dis Markers. 2023;2023:9949047. https://doi.org/10.1155/2023/9949047

11. Zhao Z, Ming Y, Li X, Tan H, He X, Yang L, et al. Hyperglycemia Aggravates Periodontitis via Autophagy Impairment and ROS-Inflammasome-Mediated Macrophage Pyroptosis. Int J Mol Sci. 2023;24(7):6309. https://doi.org/10.3390/ijms24076309

12. Konečná B, Chobodová P, Janko J, Baňasová L, Bábíčková J, Celec P, et al. The Effect of Melatonin on Periodontitis. Int J Mol Sci. 2021;22(5):2390. https://doi.org/10.3390/ijms22052390

13. Gurbuz ES, Guney Z, Kurgan S, Balci N, Serdar MA, Gunhan M. Oxidative Stress and FOXO-1 Relationship in Stage III Periodontitis. Clin Oral Investig. 2024;28(5):267. https://doi.org/10.1007/s00784-024-05670-x

14. Jos P, Teles L, Ferreira B, Ara E. Patent Mining on the Use of Antioxidant Phytochemicals in the Technological Development for the Prevention and Treatment of Periodontitis. Antioxidants. 2024;13(5):38790671. https://doi.org/10.3390/antiox13050000

15. Karaca B, Yilmaz M, Gursoy UK. Targeting Nrf2 with Probiotics and Postbiotics in the Treatment of Periodontitis. Biomolecules. 2022;12(5):729. https://doi.org/10.3390/biom12050729

16. Marfiian OV, Demkovych AY, Bondarenko YI, Yaremchuk OZ. Modern views on the etiology and role of microbial persistence in the development of inflammatory processes in the periodontal complex (review). Medicni Perspektivi. 2024;29(3):27-35. https://doi.org/10.26641/2307-0404.2024.3.313482

17. Čižmárová B, Tomečková V, Hubková B, Hurajtová A, Ohlasová J, Birková A. Salivary Redox Homeostasis in Human Health and Disease. Int J Mol Sci. 2022;23(16):9168. https://doi.org/10.3390/ijms23169168

18. Guabello G, Zuffetti F, Ravidà A, Deflorian M, Carta G, Saleh MHA, et al. Avoiding implant-related complications in medically compromised patients with or without unhealthy lifestyle / Elevated oxidative stress. Periodontol 2000. 2023;93(1):329-349. https://doi.org/10.1111/prd.12503

19. Maquera-Huacho PM, Spolidorio DP, Manthey J, Grenier D. Effect of Hesperidin on Barrier Function and Reactive Oxygen Species Production in an Oral Epithelial Cell Model, and on Secretion of Macrophage-Derived Inflammatory Mediators during Porphyromonas gingivalis Infection. Int J Mol Sci. 2023;24(13):10850. https://doi.org/10.3390/ijms241310850

20. Georgiou AC, Ulloa PC, Kessel GMH Van, Crielaard W, Waal SV Van Der. Reactive oxygen species can be traced locally and systemically in apical periodontitis: A systematic review. Arch Oral Biol. 2021;129:105167. https://doi.org/10.1016/j.archoralbio.2021.105167

21. Rapone B, Ferrara E, Qorri E, Inchingolo F, Isola G, Dongiovanni P, et al. Research efficacy of gaseous ozone therapy as an adjuvant to periodontal treatment on oxidative stress mediators in patients with type 2 diabetes: a randomized clinical trial. BMC Oral Health. 2023;23(1):290. https://doi.org/10.1186/s12903-023-02980-y

22. Buranasin P, Kominato H, Mizutani K, Mikami R, Saito N. Influence of Reactive Oxygen Species on Wound Healing and Tissue Regeneration in Periodontal and Peri-Implant Tissues in Diabetic Patients. Antioxidants. 2023;12(9):1750. https://doi.org/10.3390/antiox12091750

23. Chen K, Ma S, Deng J, Jiang X, Ma F, Li Z. Ferroptosis: A New Development Trend in Periodontitis. Cells. 2022;11(21):3349. https://doi.org/10.3390/cells11213349

24. Ramos-Junior ES, Carolina A. Mitochondrial function in oral health and disease. J Immunol Methods. 2024;532:113729. https://doi.org/10.1016/j.jim.2024.113729

25. Varma SR, Ani OHAA, Narayanan JK, Mathew A. The role of Mitofusin-1 and Mitofusin-2 in periodontal disease: a comprehensive review. Front Oral Health. 2025;6:1540178. https://doi.org/10.3389/froh.2025.1540178

26. Dong Z, Wu L, Hong H. Mitochondrial Dysfunction in the Pathogenesis and Treatment of Oral Inflammatory Diseases. Int J Mol Sci. 2023;24(20):15483. https://doi.org/10.3390/ijms242015483

27. Zheng T, Lu F, Wu P, Chen Y, Zhang R, Li X. Ferroptosis and cuproptosis in periodontitis: recent biological insights and therapeutic advances. Front Immunol. 2025;16:1526961. https://doi.org/10.3389/fimmu.2025.1526961

28. Ying J, Zhang K, Huang Y, Zhu X, Ruan Y, Lin H, et al. Molecular hydrogen: Mechanism against oxidative stress and application in periodontitis: A review. Medicine (Baltimore). 2025;104(10):e41800. https://doi.org/10.1097/MD.0000000000041800

29. Yang K, Yang Y, Long T, Wang X, Chen Y, He C, et al. Hyperhomocysteinaemia aggravates periodontitis by suppressing the Nrf2/HO-1 signalling pathway. Redox Rep. 2025;30(1):2475691. https://doi.org/10.1080/13510002.2025.2475691

30. Ferrara E, Albenzio AD, Bassignani J, Di Tanna I, Murmura G, Balice G. The Periodontal – Cardiovascular Disease Association: Molecular Mechanisms and Clinical Implications. Int J Mol Sci. 2025;26(1):150. https://doi.org/10.3390/ijms26010150

31. Lv X, Han X, Yang Y, Ma Y, Wang Y, Zhang K. Hypochlorous acid solution serves as a potential anti-biofilm therapy for periodontitis via targeting quorum sensing of periodontal pathogens. J Oral Microbiol. 2025;17(1):2458806. https://doi.org/10.1080/20002297.2025.2458806

DECLARATION OF CONTRIBUTIONS

“Conceptualization and design: María Carrasco, Carlos Naula; Literature review: María Carrasco, Carlos Naula; Methodology and validation: María Carrasco, Carlos Naula; Formal analysis: María Carrasco, Carlos Naula; Investigation and data collection: María Carrasco, Carlos Naula; Resources: María Carrasco, Carlos Naula; Data analysis and interpretation: María Carrasco, Carlos Naula; Writing – original draft preparation: María Carrasco, Carlos Naula; Writing – review and editing: María Carrasco, Carlos Naula; Supervision: María Carrasco, Carlos Naula; Project administration: María Carrasco, Carlos Naula; Funding acquisition: Not applicable.”

CONFLICTS OF INTEREST

The authors declare that there were no conflicts of interest during the conduct of the research. The manuscript was submitted exclusively to the Scientific Journal “Especialidades Odontológicas UG” for review and publication.

FUNDING

The authors declare that the research was conducted using their own funds.

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) License. Its use, distribution, or reproduction in other media is permitted, provided that appropriate credit is given to the original author(s) and copyright holder, and that the original publication in this journal is cited in accordance with accepted academic practices. Any use, distribution, or reproduction that does not comply with these terms is prohibited.

HOW TO CITE:

Carrasco Alvarado, ME. Naula Vicuña, CR. Oxidative Stress as an Etiopathogenic Factor in Periodontal Disease. Revista Científica Especialidades Odontológicas UG. 2026:9(2):64-76