Phytochemicals in Treatment of Periodontal Disease: A Review of Mechanisms and Roles

Introduction

Periodontitis, a chronic infection from plaque biofilms, is marked by inflammation and gradual loss of tooth-supporting tissues. It features gingival bleeding, periodontal pocket formation, and tissue periodontal degradation. Severe periodontitis can cause tooth mobility and loss, compromising both function and aesthetics, and it is intricately linked with various systemic diseases [1]. Periodontitis arises predominantly from oral plaque biofilm dysbiosis, where resident microorganisms initiate a localized inflammatory response, releasing proinflammatory cytokines and activating host proteases. Additionally, microbial virulence factors and an overactive host immune response exacerbate tissue damage. This leads to plaque biofilm expansion along the root surface, fueling periodontitis progression and establishing a vicious cycle that can result in tooth loss [2]. Treatment of periodontitis involves 4 main aspects: (1) reducing the dental plaque biofilm, (2) mitigating the inflammatory response, (3) promoting periodontal tissue regeneration, and (4) controlling risk factors, such as tobacco use [3]. However, conventional treatments, such as improving oral hygiene, controlling dental biofilms, mechanical plaque removal, and using antimicrobial agents, face challenges like antibiotic resistance and limited tissue regeneration [4]. Consequently, numerous researchers continue to explore novel approaches for treating periodontitis.

Phytochemicals are a diverse group of biologically active secondary metabolites naturally occurring in plants, renowned for their medicinal and nutritional properties. These compounds, including terpenoids, alkaloids, flavonoids, and polyphenols, have distinct chemical structures and functional groups that underpin their pharmacological versatility. They exhibit a wide range of biological activities, such as anti-inflammatory, antimicrobial, antiviral, anticancer, analgesic, and immunomodulatory effects. Their high potency and target specificity enable the development of drugs requiring lower therapeutic doses with reduced systemic toxicity, making them promising candidates for modern drug discovery [5]. Currently, phytochemicals are being explored and developed as clinical candidates for treating various conditions [6].

By integrating the pathogenesis of periodontitis with current research, we reviewed the therapeutic potential of phytochemicals in 3 key areas: (1) inhibiting periodontal pathogenic microorganisms, (2) alleviating inflammatory response of periodontal tissues, and (3) promoting periodontal tissue regeneration. The primary objective of this review is to evaluate the multifaceted roles of phytochemicals in combating periodontitis and to highlight their promise as novel therapeutic agents.

Phytochemicals Inhibit Periodontal Pathogenic Microorganisms

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P. gingivalis, a key pathogen in periodontitis, colonizes oral tissues, evades immune responses, and secretes virulence factors like endotoxins and gingipains, which trigger inflammation and tissue damage. It also disrupts the oral microbiome, exacerbating periodontal disease [10]. Phytochemicals combat P. gingivalis through 3 main mechanisms: 1) Membrane Disruption: Phytochemicals like epigallocatechin-3-gallate(EGCG) [11] and hibiscetin [12] damage P. gingivalis’s membrane via oxidative stress and hydrogen peroxide generation. Hydrophobic compounds such as coumarins [13] integrate into the membrane, compromising its integrity. Additionally, alophyllum inophyllum oil (CIO) [14] and EGCG [15] enhance human β-defensins, further destabilizing the membrane. 2) Metabolic Interference: Phytochemicals like black cherry seed extract and quercetin block hemagglutinin activity, inhibiting nutrient uptake, while catechin and cinnamon extracts disrupt quorum sensing, impairing growth and invasiveness [16,17]. 3) Biofilm Inhibition: Epimedium [18] and rice protein [19] extracts hinder biofilm formation by blocking adhesion and gingipain activity, while capsaicin [20] and carvacrol [21] disrupt biofilm integrity and damage mature biofilms. These mechanisms demonstrate phytochemicals’ multifaceted potential incombating P. gingivalis and treating periodontitis.

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A. actinomycetemcomitans, a gram-negative anaerobic bacterium, is associated with aggressive periodontitis. It colonizes subgingivally, evades immune defenses, and damages periodontal tissues through virulence factors like leukotoxin A (LtxA), which targets immune cells, and cytolethal distending toxin (CDT), which induces DNA damage. Outer membrane vesicles deliver these toxins and modulate immune responses. The bacterium also uses autoinducer-2 (AI-2) for quorum sensing, coordinating biofilm formation with other bacteria and stimulates bone resorption through capsular polysaccharide, chaperone 60 (GroEL), and lipid A-associated proteins [22]. The increasing resistance of A. actinomycetemcomitans to conventional antimicrobials [23] has shifted the research focus toward phytochemicals, which are less prone to resistance development and have fewer adverse effects. Phytochemicals also show promise in enhancing antibiotic efficacy when used in combination. Additionally, extracts from garlic, guava, oleoresin, curcumin, and xanthohumol have demonstrated inhibitory effects against this bacterium [24]. However, most studies on phytochemicals’ antimicrobial activity have been in vitro, underscoring the need for further research to fully elucidate their mechanisms of action.

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T. forsythia, a key member of the ‘red complex’ alongside P. gingivalis and T. denticola, plays a significant role in periodontal disease progression. It adheres to host cells via OmpA-like proteins and neutralizes salivary acids with secreted proteins, enhancing its growth by degrading host proteins. The bacterium also evades immunity by degrading components of both innate and adaptive immune systems. Through surface lipoproteins, it influences coagulation and fibrinolysis, inducing host cell apoptosis and facilitating colony formation. Additionally, its synergy with F. nucleatum in forming hybrid biofilms enhances tissue invasion [25]. Anthocyanins in blackcurrant [26] and cranberry extracts [27] inhibit proteases, protecting the gingival matrix and alleviating enzyme-mediated tissue destruction in periodontitis. Despite its significant role in periodontal pathogenesis, T. forsythia remains understudied due to its challenging culture requirements and genetic manipulation difficulties. Thus, further research into the antibacterial effects of phytochemicals against T. forsythia is essential.

Phytochemicals show significant potential in inhibiting periodontal pathogens, suppressing virulence factors, eliminating free-floating bacteria, and disrupting dental plaque biofilms (Figure 1A). As evidenced by clinical trials, phytochemicals, including curcumin [28] and tea tree oil [29], demonstrate potent antimicrobial activity against key periodontal pathogens. When used as adjuncts to mechanical plaque removal therapies (eg, scaling and root planing), they significantly enhance improvements in core clinical parameters such as probing depth reduction and clinical attachment gain. However, research on phytochemicals remains at a nascent stage, constrained by 3 critical limitations: unidentified bioactive constituents, predominant reliance on short-term in vitro assays, and inadequate longitudinal efficacy data. To advance this field, future studies must prioritize: (1) large-scale randomized controlled trials with extended follow-up periods; (2) mechanistic investigations isolating core bioactive compounds and their synergies; (3) optimization of targeted delivery systems; and (4) in vivo validation accounting for oral biofilm complexity – all essential for establishing clinically safe applications.

Phytochemicals Alleviate Inflammation in Periodontal Tissues

PHYTOCHEMICAL MODULATION OF THE NF-κB PATHWAY:

The NF-κB pathway, a key inflammation mediator, involves proteins like RelA (p65), RelB, c-Rel, NF-κB1 (p50), and NF-κB2 (p52). Activation triggers IκB phosphorylation and degradation, enabling NF-κB nuclear translocation and expression of proinflammatory mediators (eg, IL-1, IL-6, IL-8, PGE2). In periodontitis, P. gingivalis LPS elevates p50 and p65 activation, increasing the p50/p65 ratio and worsening tissue damage. IL-1β and IL-18 amplify NF-κB, upregulating MMPs and prostaglandins, impairing periodontal cell proliferation [31]. Therapeutic interventions targeting p50 and p65 within the NF-κB signaling pathway hold promise for periodontitis treatment [32]. For example, Curcumin inhibits p50 phosphorylation and upregulates TGF-β, while derivatives like CMC2.24 modulate inflammatory mediators and reduce bone loss [33]. Berberine suppresses NF-κB p65, downregulating TNF-α, IL-1β, and IL-10, mitigating inflammation and bone resorption [34]. Caffeic acid phenethyl ester (CAPE) inhibits TLR4/MyD88 and NF-κB pathways, reducing IL-6, IL-8, iNOS, and COX-2 production in gingival fibroblasts [35].

PHYTOCHEMICAL MODULATION OF THE JAK/STAT SIGNALING PATHWAY:

The JAK/STAT pathway mediates cytokine-driven inflammation via JAK-mediated receptor phosphorylation and STAT nuclear translocation, regulating cytokines (eg, IFN-γ, TNF-α, IL-1, IL-4, IL-6, IL-10) critical in periodontitis [36]. Activation of STAT1 and STAT3 in periodontitis models increases IL-6 and TNF-α, upregulating SOCS1 and SOCS3 as negative feedback regulators [37]. P. gingivalis infection upregulates JAK1 and STAT3 in gingival epithelial cells, promoting apoptosis [38]. Given the JAK/STAT pathway’s central role in inflammatory conditions such as periodontitis, there is an ongoing quest for targeted therapeutics. Mangiferin, a polyphenolic constituent of phytochemicals, exhibits anti-inflammatory effects. In a murine model of P. gingivalis-induced periodontitis, mangiferin treatment notably reduced alveolar bone loss, TNF-α levels, and JAK1-STAT1/3 phosphorylation in gingival epithelial cells [39]. Resveratrol shifts macrophage polarization from M1 to M2 by regulating p-STAT3 and p-STAT1, reducing production of reactive oxygen species (ROS) and IL-1β [40].

PHYTOCHEMICAL MODULATION OF THE MAPK SIGNALING PATHWAY:

The MAPK pathway regulates cellular responses to inflammatory cytokines (eg, IL-1, TNF-α, IL-6) and stress. In periodontitis, LPS activates p38 MAPK, modulating cytokine expression and reducing osteogenic potential in periodontal ligament stem cells (PDLSCs) [41]. P. gingivalis LPS triggers ERK1/2 and p38 MAPK activation, increasing IL-8 expression in periodontal fibroblasts [42]. Given the MAPK pathway’s key role in inflammatory cytokine regulation, numerous studies have indicated that targeting the MAPK pathway, particularly p38 MAPK, could be an effective approach for periodontitis treatment [43]. For instance, quercetin has been shown to inhibit the activation of ERK1/2, p38, and c-JNK in human gingival fibroblasts treated with P. gingivalis LPS. This inhibition impacts MAPK activation, COX-2 expression, IL-1β production, and PGE2 synthesis, suggesting quercetin’s potential role in modulating periodontitis development [44]. Shikonin, derived from comfrey (Radix arnebiae) has demonstrated its capacity to mitigate inflammation in LPS-challenged human periodontal ligament cells (hPDLCs) via the ERK pathway, effectively suppressing LPS-induced expression of IL-1, IL-6, TNF-α, MMP-2, MMP-9, and COX-2 [45]. Genistein, a phytoestrogen from soybeans, regulates MAPK activation in IL-β-stimulated human periodontal cells via GPR30, potentially influencing the course of periodontitis [46].

PHYTOCHEMICAL MODULATION OF THE WNT SIGNALING PATHWAY:

Wnt signaling, including canonical (β-catenin-dependent) and non-canonical pathways, influences periodontitis by regulating bone loss and osteogenic differentiation [47].. For example, LPS and EMMPRIN activate the Wnt/β-catenin pathway in gingival cells, suppressing MMP-2 and MMP-9 expression [48]. For the Wnt signaling pathway, numerous phytochemicals have shown potential therapeutic effects in treating periodontitis through its modulation. In a periodontitis rat model, Calendula officinalis (CLO) extract reversed bone resorption, collagen breakdown, and restored WNT10b and β-catenin expression, suggesting Wnt pathway modulation [49]. Luteolin reduces inflammatory mediators (IL-1β, TNF-α, MMP-1, MMP-2, MCP-1) and enhances osteogenesis via Wnt/β-catenin signaling [50].

PHYTOCHEMICAL MODULATION OF THE PI3K/AKT SIGNALING PATHWAY:

The PI3K/Akt pathway regulates inflammation in periodontitis. Sema3A promotes M1-to-M2 macrophage polarization, activating PI3K/AKT/mTOR and reducing iNOS, IL-12, TNF-α, and IL-6 [51]. It also mediates anti-inflammatory effects via heme oxygenase-1 (HO-1) [52]. Targeting PI3K/Akt with phytochemicals is a promising therapeutic strategy. Populin, a flavonoid isolated from botanical sources, inhibits AKT signaling and COX-2 expression in gingival fibroblasts exposed to Streptococcus haematobium lipophosphatidic acid (LTA) [53]. Similarly, lignans suppress Akt phosphorylation and NO production in A. actinomycetemcomitans-LPS-stimulated fibroblasts, demonstrating their potential in modulating inflammatory pathways for periodontitis management [54].

PHYTOCHEMICAL MODULATION OF THE NRF2/HO1 SIGNALING PATHWAY:

The Nrf2/HO1 pathway is pivotal in antioxidant and anti-inflammatory responses in periodontitis, making it a promising therapeutic target. In an oxidative stress model of periodontitis induced by hydrogen peroxide in hPDLSCs, the exposure led to elevated MDA levels, indicating increased lipid peroxidation. Concurrently, there was a dose-dependent upregulation of Nrf2 and its target genes HO-1, NAD(P)H: quinone oxidoreductase 1 (NQO1), and γ-glutamylcysteine synthase (γ-GCS) [55]. Elevated Nrf2 levels in periodontitis patients correlate with alveolar bone recovery after Nrf2 agonist treatment, suggesting its modulation could mitigate oxidative stress and enhance anti-apoptotic mechanisms, offering a potential strategy for periodontitis management [56]. Resveratrol has been shown to mitigate alveolar bone resorption and activate the Sirt1/AMPK and Nrf2/antioxidant defense pathways in inflamed gingival tissues of a rat ligature-induced periodontitis model. Furthermore, it modulates systemic biomarkers of oxidative stress and inflammation, including 8-hydroxydeoxyguanosine, dityrosine, NO metabolism, nitrotyrosine, and proinflammatory cytokines [57]. Baicalein mitigates ROS, preserves mitochondrial function, and enhances pNrf2 nuclear translocation and subsequent target gene expression, reducing bone loss [58]. Ginkgo biloba extract suppresses proinflammatory mediators and MAPK activation while enhancing HO-1 expression and Nrf-2 nuclear translocation in P. gingivalis LPS-stimulated macrophages [59].

Unlike single-target conventional drugs, phytochemicals function as multi-target agents against periodontal inflammation [60] (Figure 1B). Curcumin concurrently modulates NF-κB, MAPK, and JAK-STAT signaling, while resveratrol, baicalein, and berberine employ distinct anti-inflammatory modalities. Critically, Nrf2-regulated HO-1 inhibits NF-κB via heme-to-bilirubin conversion, suppressing adhesion molecules (E-selectin, VCAM-1). Stress-induced cytokines activate MAPKs, inducing Nrf2/HO-1 expression, revealing bidirectional crosstalk. This systems-level polypharmacology underlies NP efficacy but complicates understanding the mechanisms and clinical translation due to target promiscuity.

Phytochemicals Promote Periodontal Tissue Regeneration

PHYTOCHEMICALS PROMOTE BONE REGENERATION AND FORMATION:

Alveolar bone is a critical support structure for periodontal tissues. Under normal conditions, it maintains a dynamic balance of bone metabolism involving osteoblast differentiation and osteoclast regulation. Periodontal disease disrupts this balance, with inflammatory factors, excessive osteoclast activity, and suppressed osteoblast function causing rapid bone loss. Recently, phytochemicals have gained attention for their potential in bone regeneration and formation by enhancing osteogenic differentiation of stem cells and improving the osteogenic microenvironment.

PHYTOCHEMICALS PROMOTE OSTEOGENIC DIFFERENTIATION OF STEM CELLS:

Stem cell-based regeneration is a central focus in periodontal tissue repair, with stem cell-based tissue engineering and regenerative medicine offering promising avenues for achieving periodontal regeneration [61]. Various stem cells, including bone marrow mesenchymal stem cells (BMSCs), periodontal stem cells, pulp stem cells, apical papilla stem cells, gingival mesenchymal stem cells, adipose mesenchymal stem cells, and dental follicle stem cells, have demonstrated the ability to promote periodontal tissue regeneration [62]. These cells can differentiate into diverse periodontal tissue components, facilitating the regeneration of alveolar bone, cementum, and periodontal ligament under conditions. Recent studies show that certain phytochemicals enhance stem cell activity, proliferation, and differentiation, further supporting their potential in regenerative strategies [63].

Periodontal stem cells can differentiate into osteoblasts, fibroblasts, and cementoblasts, contributing to alveolar bone, periodontal ligament, and odontoblast formation [64]. Phytochemicals like osthole [65] and naringenin [66] promote their proliferation and osteogenic differentiation by upregulating markers such as ALP, RUNX2, OCN, and COL1A2. Kaempferol [67] activates the Wnt/β-catenin pathway, enhancing osteogenic differentiation and extracellular matrix synthesis.

Human periodontal ligament cells are essential for both the pathological processes and the regeneration of the periodontal ligament during periodontitis; these cells exhibit osteogenic and odontogenic potential and inhibit preosteoclast differentiation [68]. Asiaticoside activates the Wnt/β-catenin pathway, enhancing ALP activity and osteogenic differentiation [69]. Furthermore, EGCG improves proliferation, mineralization, and osteogenic marker expression (eg, RUNX2, BMP2, OSX, OCN) in these cells [70].

BMSCs are a population of human non-hematopoietic stem cells characterized by self-renewal, clonogenicity, and multilineage potential to differentiate into osteoblasts, adipocytes, and chondrocytes [71]. There is a rising trend in using BMSCs for periodontal tissue regeneration, particularly in conjunction with phytochemicals. Icariin upregulates ALP, BSPII, and RUNX2 via the Wnt/β-catenin pathway while inhibiting adipogenic differentiation [72]. Additionally, 5′-hydroxy auraptene (5′-HA) promotes BMSC osteogenic differentiation in a dose-dependent manner by activating the BMP signaling pathway through SMAD4 upregulation [73]. Fucoidan augments the proliferation and osteogenic differentiation of human BMSCs, offering an innovative strategy for the treatment of alveolar bone defects in periodontal diseases [74].

PHYTOCHEMICALS IMPROVE THE OSTEOGENIC MICROENVIRONMENT:

Enhancing the osteogenic microenvironment is crucial for periodontal tissue regeneration, as it promotes osteoblast maturation and differentiation, facilitating new bone synthesis and improving bone quality. Phytochemicals have shown promise in optimizing this microenvironment, aiding periodontal tissue recovery through 5 key mechanisms: promoting osteoblast differentiation, inhibiting osteoclast formation, reducing inflammation, mitigating oxidative stress, and managing hyperglycemia.

PHYTOCHEMICALS PROMOTING OSTEOBLAST DIFFERENTIATION:

Osteoblasts, essential for bone repair, play a pivotal role in periodontal tissue regeneration. Phytochemicals such as betulinic acid and baicalin have demonstrated the ability to enhance the osteogenic microenvironment, which is crucial for periodontal tissue regeneration. Betulinic acid increases ALP activity and osteogenic gene expression, synergizing with BMP2 to boost osteogenesis [75]. Baicalin promotes osteogenic differentiation via the Wnt/β-catenin pathway, increasing ALP, RUNX2, and calcium deposition, highlighting its potential in periodontal regeneration [76].

PHYTOCHEMICALS INHIBIT OSTEOCLAST FORMATION AND DIFFERENTIATION:

Phytochemicals suppress the differentiation of osteoclast-like cells from RANKL-stimulated RAW264.7 cells, human peripheral blood mononuclear cells (PBMCs), and bone marrow macrophages (BMMs), which is crucial for reducing periodontal bone loss. For example, Chalcone T4 prevents osteoclast formation by downregulating osteoclastogenic markers and suppressing RANKL-induced osteoclast differentiation. It enhances osteogenic potential by upregulating ALP, RUNX2, and mineralization in MC3T3-E1 cells. In vivo studies confirm its efficacy in reducing periodontitis-related bone loss and inflammation [77]. Protocatechuic acidin inhibits osteoclastogenesis by reducing RANKL-induced differentiation of BMMs into osteoclasts and suppressing bone resorption [78].

PHYTOCHEMICALS AMELIORATE THE INFLAMMATORY MICROENVIRONMENT:

Inflammation can impair stem cell function and hinder tissue regeneration. Modulating inflammatory mediators to improve the inflammatory microenvironment is crucial for enhancing bone regeneration. Thus, reducing inflammation is essential for the repair of periodontal tissues [79]. Phytochemicals can inhibit inflammatory responses through various signal pathways, thereby ameliorating the inflammatory microenvironment. For example, proanthocyanidins reverse TNF-α-induced inhibition of osteogenesis by blocking the NF-κB pathway [80], quercetin protects periodontal stem cells from inflammation by inhibiting the NF-κB/NLRP3 pathway [81], and notoginsenoside R1(NTR1) promotes osteoblast function under TNF-α-induced inflammation by activating the Wnt/β-catenin pathway and inhibiting NF-kB [82].

PHYTOCHEMICALS MITIGATE THE HYPEROXIC ENVIRONMENT:

Excessive ROS accumulation accelerates cellular senescence and impairs osteogenic differentiation [83]. Therefore, a hyperoxic environment is detrimental to periodontal bone tissue regeneration and repair. Phytochemicals can ameliorate hyperoxic conditions to foster bone repair. Quercetin enhances antioxidant defenses via the NRF2 pathway, reducing oxidative damage and preserving osteogenic potential [84]. Curcumin reduces ROS and apoptosis, promoting osteogenic differentiation through the ERK1/2/FoxO3a pathway, improving bone repair in rat cranial defect models [85].

PHYTOCHEMICALS ALLEVIATE THE HYPERGLYCEMIC ENVIRONMENT:

High levels of glucose and late glycosylation end products in periodontal tissues lead to increased expression of inflammatory mediators and accelerated destruction of periodontal tissues [86]. Controlling hyperglycemia is crucial for periodontal health, and phytochemicals offer a new treatment approach by improving the glycemic environment and enhancing osteogenic cell differentiation. Phytochemicals like hesperetin and berberine enhance osteogenic differentiation under high-glucose conditions via PI3K/Akt and Wnt/β-catenin pathways [87,88]. Astaxanthin alleviates oxidative stress through Nrf2 signaling, promoting osteogenic differentiation and protecting against periodontal damage in diabetic models [89].

In summary, phytochemicals enhance the osteogenic microenvironment and rejuvenate osteogenic differentiation through diverse mechanisms, offering innovative strategies for periodontal tissue regeneration and repair.

PHYTOCHEMICALS PROMOTE SOFT-TISSUE REGENERATION:

Promoting periodontal soft-tissue regeneration is crucial in treating periodontal diseases, although research on phytochemicals directly enhancing this process remains limited. Aloe vera, known for its wound-healing properties, contains acetylated mannan, which aids periodontal soft-tissue regeneration [90]. Studies show acetylated mannan boosts gingival fibroblast proliferation and enhances the expression of kGF-1, VEGF, and type I collagen, accelerating oral wound healing in rats [91]. Shikonin promotes fibroblast proliferation, migration, and collagen synthesis via the ERK1/2 pathway, upregulating VEGF and fibronectin expression, indicating its potential for periodontal tissue repair [92]. Vanillin exhibits anti-inflammatory and regenerative effects by reducing proinflammatory cytokines (eg, IL-6, IL-8, TNF-α), modulating oxidative stress, and activating the nAChRα7 pathway, supporting gingival fibroblast regeneration [93]. These findings underscore the potential of phytochemicals in promoting periodontal soft-tissue repair through direct fibroblast activation and anti-inflammatory mechanisms.

In conclusion, phytochemicals have shown potential in increasing stem cell activity, regulating the expression of osteogenic differentiation markers, mitigating adverse effects on cells in inflamed, oxidative stress, and high-glucose environments, and improving the osteogenic microenvironment (Figure 1C). This presents a novel approach for clinically addressing alveolar bone loss and enhancing periodontal tissue repair and regeneration. Nevertheless, the evidence remains limited, and further in vivo investigations and clinical trials are necessary to validate the feasibility of these phytochemicals in treating periodontal disease and promoting periodontal tissue regeneration.

Future Directions

Phytochemicals, rooted in a rich medicinal heritage, exhibit significant therapeutic potential due to their biocompatibility, making them promising candidates for clinical applications [94]. Phytochemicals such as curcumin-based gels and mouthwashes have shown promise in reducing probing depth and clinical attachment loss in patients with chronic periodontitis [95], complementing their antimicrobial and anti-inflammatory effects observed in animal models [96].

Advances in science and technology have accelerated the development of novel phytochemical-based formulations. For instance, nanotechnology enables targeted delivery, sustained release, and enhanced bioavailability, markedly improving therapeutic outcomes [97]. Despite these advances, many phytochemicals and their nanoformulations remain underexplored. Future research should prioritize isolating and purifying bioactive compounds to clarify their pharmacological properties and mechanisms. Additionally, rigorous animal studies and clinical trials are essential to validate their efficacy and safety. These efforts will pave the way for integrating phytochemicals and their advanced formulations into mainstream periodontitis prevention and treatment, potentially transforming periodontal care.

Conclusions

This review underscores the multifaceted roles of phytochemicals in periodontitis treatment, emphasizing their ability to suppress periodontal pathogens, mitigate inflammation, and enhance tissue regeneration (Figure 1).