The role of Lyn in immunity and chronic inflammation: Implications for periodontitis

Abstract

Lyn kinase, a critical immune regulator, is well-established in systemic autoimmune diseases, but its role in periodontitis remains unclear. This narrative review synthesizes literature up to July 2025 from PubMed, Scopus, and Web of Science to examine the immunoregulatory functions of Lyn and discuss its potential role in periodontitis. Current evidence indicates that Lyn may be relevant to multiple processes implicated in periodontal pathogenesis, including B-cell signaling, Th17-related inflammatory networks, neutrophil-associated responses, NF-κB- and IL-1β-related inflammation, and inflammatory bone resorption. However, direct periodontal evidence remains limited and is derived largely from transcriptomic, bioinformatic, and cross-disease studies, together with mechanistic extrapolation from other inflammatory settings. Accordingly, Lyn should currently be regarded not as an established mechanistic driver, but as a hypothesis-generating molecular candidate in periodontitis. This review proposes a periodontitis-centered conceptual framework for future periodontal-specific investigation of Lyn.

1. Introduction

Chronic periodontitis is an infectious inflammatory disease initiated by dental plaque accumulation, which gradually leads to the destruction of tooth-supporting tissues—including the gingiva, periodontal ligament, cementum, and alveolar bone. ¹ As a persistent source of infection, periodontitis is recognized as an independent risk factor for various systemic conditions, such as cardiovascular diseases, cerebrovascular diseases, peripheral arterial diseases, respiratory diseases, and low birth weight. ² Moreover, it is associated with an increased risk of, and poorer prognosis for, diabetes, insulin resistance, rheumatoid arthritis, obesity, osteoporosis, and pregnancy complications.^3,4

Although current non-surgical treatments for periodontitis can control the local infection, maintaining long-term stability remains challenging. ⁵ Research indicates that host immune responses play a crucial role in disease pathogenesis. The periodontal immune microenvironment is a complex network comprising diverse cell types, extracellular matrix components, and cytokines. The epithelial barrier, innate immune cells—including neutrophils, macrophages, and dendritic cells—and antibodies present in gingival crevicular fluid constitute the first line of defense against microbial invasion. ⁶ Once this barrier is compromised, pathogenic interference triggers an exaggerated inflammatory response, affecting host cell differentiation and function, which ultimately results in the destruction of periodontal supporting tissues. Tissue damage in periodontitis is primarily driven by the host immune response rather than direct microbial activity. These processes involve key periodontal pathways related to NF-κB activation, IL-1β-centered inflammatory signaling, and osteoimmunology-associated bone resorption.^7–9

Lyn is a core member of the Src family kinases and a non-receptor tyrosine kinase widely expressed in multiple immune-related cell types.^10,11 It plays a bidirectional role in immune regulation by participating in both activating and inhibitory signaling pathways. ¹² This “molecular switch” property makes Lyn biologically relevant to chronic inflammatory diseases. However, although Lyn has been extensively studied in autoimmune and systemic inflammatory settings, direct periodontal evidence remains limited, and its precise role in periodontitis should therefore be regarded as hypothesis-generating rather than mechanistically established.

Accordingly, this narrative review aims to summarize the current understanding of Lyn in immune regulation and chronic inflammation, discuss its potential relevance to periodontitis, and propose a conceptual framework for future mechanistic investigation. To improve transparency, the literature discussed in this review was identified through searches of PubMed, Scopus, and Web of Science up to July 2025, using combinations of the terms “Lyn,” “Lyn kinase,” “periodontitis,” “immune regulation,” “chronic inflammation,” and related keywords. This review was prepared as a narrative synthesis and was revised in accordance with the principles of SANRA. ¹³ A conceptual overview of the proposed role of Lyn in periodontitis is presented in Figure 1.

Figure 1.

Conceptual overview of the proposed role of Lyn in periodontitis.

2. Characteristics of Lyn

Lyn is a Src family tyrosine kinase that exerts multiple regulatory functions in immune cells, such as B cells and neutrophils. In BCR signaling, Lyn activates downstream positive pathways while also recruiting phosphatases such as SHP1/SHIP to inhibitory receptors like CD22 and FcγRIIB,^14,15 thus negatively regulating signal intensity and preventing excessive B-cell activation. In Lyn-deficient models, B cells exhibit heightened reactivity, accompanied by elevated levels of IgG autoantibodies such as ANA, indicating Lyn’s critical role in limiting autoimmune responses. Thus, even within the same cell type, Lyn may contribute to either signal initiation or negative feedback depending on receptor context and the balance between activating and inhibitory inputs.

Although Lyn is not directly expressed in T cells, its regulation of B-cell function indirectly impacts T cell-mediated immune responses. ¹⁶ Studies ¹⁷ have shown that in Lyn-deficient mice, the activation of helper T cells (especially Th17) is enhanced, while Treg cell numbers increase but their function is impaired, leading to a breakdown in immune tolerance and the formation of a chronic inflammatory microenvironment. In a previous transcriptomic analysis conducted by our group, ¹⁸ Lyn expression in periodontitis tissues was positively correlated with Th17-related marker genes such as IL17A and RORC. However, this finding should be interpreted as associative and hypothesis-generating rather than as direct evidence that Lyn controls T-cell differentiation in periodontal lesions.

Moreover, Lyn plays a bidirectional regulatory role in neutrophils. ¹⁹ Under basal adhesive conditions, Lyn phosphorylates the ITIM domains of SIRPα and PIR-B to recruit SHP1, thereby negatively regulating integrin signaling and suppressing excessive adhesion and hyperactivation of neutrophil effector functions. ²⁰ Upon chemotactic stimulation (e.g., fMLP), Lyn is recruited to the leading edge, where it promotes activation of the CrkL–C3G–Rap1 axis, ¹⁹ modulates β2-integrin–mediated adhesion, and maintains directional migration. This regulation is essential for the accurate positioning and efficient clearance functions of neutrophils at inflammatory sites. These observations further illustrate that Lyn may either restrain excessive inflammatory activation or facilitate appropriate leukocyte responses, depending on the biologic setting.

In summary, Lyn plays a pivotal role in regulating B-cell activity, neutrophil trafficking, and the homeostasis of the inflammatory microenvironment. Taken together, these findings support viewing Lyn as a context-dependent immunoregulatory molecule rather than as a uniformly pro-inflammatory or anti-inflammatory kinase. In periodontitis, where dysbiosis-driven innate activation, adaptive immune imbalance, and inflammatory bone loss coexist, this duality may be particularly relevant and warrants periodontal-specific investigation.

Given the context-dependent role of Lyn in both activating and inhibitory immune signaling, Figure 2 provides a schematic overview of how Lyn may position cross-talk among BCR-, TLR-, integrin-, and RANKL-related pathways.

Figure 2.

Schematic overview of Lyn-associated cross-talk among BCR, TLR, integrin, and RANKL-related pathways.

3. Dual role of Lyn in autoimmune diseases

Autoimmune diseases encompass over 80 conditions, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and inflammatory bowel disease (IBD).^21,22 These disorders are characterized by immune responses that erroneously target the body’s own tissues, resulting in systemic inflammation and tissue damage. ²³ Despite extensive research, the precise pathological mechanisms underlying autoimmune diseases remain incompletely understood. In the present review, evidence from autoimmune diseases is discussed primarily as supporting immunologic context rather than as direct proof of Lyn’s role in periodontitis.

In autoimmune diseases, B cells serve as a critical interface between innate and adaptive immunity. The interaction between T cells and B cells facilitates the activation and differentiation of plasma cells, which are responsible for producing pathogenic autoantibodies. ²⁴ Activated B cells also support T cell functions by promoting the secretion of pro-inflammatory cytokines^25,26 and modulate non-immune cells through cytokines such as interleukins (e.g., IL-1, IL-6, IL-17A) and TNF-α. ²⁷ Src family protein kinases (SFKs) play vital roles in various cellular processes, including regulating B-cell growth, proliferation, and differentiation via signaling through the B-cell receptor (BCR). Within this framework, Lyn is relevant because it may participate in both activating and inhibitory signaling, depending on receptor context and downstream feedback mechanisms.

E. L'Estrange-Stranier et al., ²⁸ in their 2024 study, highlighted that Lyn, as a non-receptor protein tyrosine kinase, plays a distinctive role in immune cell signaling by mediating both activation and inhibition pathways. Mouse genetic studies reveal this duality: either decreased or heightened Lyn activity can result in autoinflammatory conditions, including lupus-like diseases. Additionally, research involving SLE patients has established links between Lyn dysregulation and the development of SLE and related autoinflammatory disorders. Consequently, these findings support the view that Lyn is a context-dependent regulator of immune homeostasis and that both insufficient and excessive Lyn activity may be pathogenic in selected immune settings.

The dual functions of Lyn are primarily mediated through its phosphorylation of different immune receptors. In activating signals, Lyn phosphorylates ITAMs of immune receptors such as the BCR, FcεRI, and FcγRI, which in turn recruit and activate downstream kinases like Syk, initiating signaling cascades that promote immune cell activation, proliferation, and differentiation. These processes are especially critical in B-cell and myeloid cell immune responses. Conversely, in inhibitory signaling pathways, Lyn phosphorylates ITIMs of inhibitory receptors such as CD22, FcγRIIB, and PD-1, leading to the recruitment and activation of phosphatases like SHP-1 and SHIP-1. These phosphatases suppress signaling pathways like BCR activation, thereby negatively regulating immune cell activation and maintaining immune tolerance. Accordingly, Lyn may be pro-inflammatory when it facilitates activating receptor signaling, but anti-inflammatory when it predominantly mediates inhibitory feedback and signal restraint.

Furthermore, rheumatoid arthritis (RA) is characterized in part by abnormal B-cell activation, inflammatory cytokine production, and loss of immune tolerance, highlighting the broader relevance of Lyn-related immune regulation in autoimmune inflammation. In addition, pharmacologic activation of the FcγRIIb/Lyn/SHP-1 pathway has been shown to inhibit B-cell activation and ameliorate collagen-induced arthritis, further supporting the immunoregulatory relevance of Lyn-associated signaling in RA.^29,30 These RA-related observations are cited here as supporting context for Lyn’s immunoregulatory potential rather than as direct evidence for periodontal disease.

Clinical evidence indicates that Lyn may serve both as a biomarker of disease activity and as a potential therapeutic target in autoimmune diseases. However, in the present review, the main value of these findings is to provide biologic plausibility for Lyn-centered immune dysregulation, while periodontal-specific functional studies remain necessary to define its actual role in periodontitis.

4. Specific mechanisms of Lyn in periodontitis

Building on the preceding discussion of autoimmune diseases and Lyn’s interactions with B cells, T cells, and neutrophils, we infer that in the immunologically driven context of periodontitis, Lyn’s potential contribution likely centers on its ability to regulate chronic inflammation and immune responses. By suppressing or activating key signaling pathways, Lyn may either mitigate or exacerbate periodontal inflammation. For example, in certain settings, Lyn activation may heighten oxidative stress and cytokine secretion, thereby promoting disease onset; in others, Lyn may curb chronic inflammatory pathways and slow disease progression. Thus, as a critical immunoregulatory molecule, Lyn’s role in periodontitis warrants close attention. Importantly, this possibility should be interpreted within the established periodontal framework of dysbiosis-driven host inflammation, in which microbial sensing, NF-κB activation, IL-1β-centered signaling, and inflammatory bone resorption are central pathogenic features rather than peripheral events.

4.1. Basis of bioinformatics research

In a previous bioinformatic study conducted by our group, ¹⁸ three periodontitis-related microarray datasets from the GEO database (GSE10334, GSE16134, and GSE23586) were compiled, encompassing gene expression profiles from periodontitis lesions and healthy gingival tissues. Raw data were preprocessed (background correction, normalization, and probe reannotation) to ensure quality. Differential expression analysis was performed on GSE10334 and GSE16134 using the limma package, identifying genes significantly up- or downregulated in periodontitis (P < 0.05, fold change > 1.5). In total, 1,424 differentially expressed genes were identified, with Lyn, PRKCD, and PTK2B notably upregulated in periodontal tissues. Subsequent GO and KEGG enrichment analyses revealed significant enrichment in immune-related functions and pathways, particularly the chemokine signaling pathway (hsa04062). Within this pathway, Lyn, PRKCD, and PTK2B emerged as key regulatory genes, suggesting their potential relevance to immune dysregulation in periodontitis and providing a theoretical foundation and screening rationale for subsequent experimental validation. Other cross-disease bioinformatic studies have also identified Lyn as a potential shared biomarker in periodontitis-related inflammatory networks, further supporting its possible relevance at the transcriptomic level.^31–36

4.2. Hypothesized mechanisms of Lyn in periodontitis

Existing transcriptomic data and immune deconvolution analyses ¹⁸ indicate an altered immune microenvironment in periodontitis tissues, characterized chiefly by a reduced proportion of regulatory T (Treg) cells and an expansion of T helper 17 (Th17) cells. Treg cells are pivotal for maintaining immune homeostasis and restraining excessive inflammation; their decline may weaken immunosuppressive function and thereby exacerbate periodontal tissue injury. Conversely, Th17 expansion is closely linked to heightened inflammation, as these cells secrete pro-inflammatory mediators (e.g., IL-17A) that further disrupt periodontal homeostasis.^37,38

Moreover, emerging evidence highlights an important role for Lyn within the immunosuppressive microenvironment of periodontitis. In our previous transcriptomic analysis, ¹⁸ a moderate positive correlation was observed between Lyn expression and Th17 signature genes (e.g., RORC and IL17A), suggesting that Lyn may participate in Th17-related inflammatory networks. However, this association should be interpreted as hypothesis-generating rather than mechanistically definitive, and it is not yet sufficient to conclude that Lyn directly modulates Th17 cell differentiation or promotes periodontal inflammation. As a pivotal signaling molecule, Lyn’s precise regulatory mechanisms in Th17 differentiation warrant further investigation and may inform the development of targeted therapeutic strategies. Taken together, these findings provide preliminary support for further periodontal-specific functional studies of Lyn. Similar to other immune mediators in periodontitis, the biologic effect of Lyn may depend on inflammatory context rather than being uniformly pathogenic.

In addition, periodontitis is now understood as a dysbiosis-associated inflammatory disease in which microbial products activate pattern-recognition receptors, especially TLR2 and TLR4, thereby triggering downstream NF-κB-related signaling and promoting the release of pro-inflammatory mediators such as IL-1β, IL-6, and TNF-α. Recent periodontal studies further support the functional importance of the inflammasome–IL-1β axis in inflammatory bone loss, showing that inflammasome targeting can reduce inflammatory cell infiltration, dampen RANK pathway-related osteoclastogenesis signaling, and lessen bone resorption in experimental periodontitis. Although these findings do not demonstrate a direct mechanistic role of Lyn in periodontal lesions, they strengthen the biological relevance of pathways in which Lyn-related regulation has been implicated in other inflammatory settings.^8,9,39,40

Converging studies indicate that Lyn functions upstream in the BCR signaling cascade. By phosphorylating ITAMs on the BCR complex, Lyn creates docking sites for spleen tyrosine kinase (Syk). Syk then binds these phospho-ITAMs via its SH2 domains and is further phosphorylated by Lyn, primarily at Y525/Y526, thereby activating its kinase activity. Activated Syk serves as a central hub that propagates downstream BCR signaling. ⁴¹ Thus, Lyn and Syk operate in tight functional concert within the BCR pathway. Although both are NRTKs predominantly expressed in hematopoietic cells and play key roles in immune cell signal transduction, they occupy distinct positions and are governed by different regulatory mechanisms within this signaling axis.

Studies ⁴² employing SH3BP2- and Syk-deficient mouse models, together with the pharmacologic inhibitor GS9973, have revealed a pivotal role for the SH3BP2–Syk axis in periodontitis-associated alveolar bone resorption. SH3BP2 is an adaptor protein predominantly expressed in hematopoietic cells (e.g., macrophages and osteoclast precursors) that participates in intracellular signaling by interacting with multiple molecules, including Syk, VAV, Lyn, and PLCγ. These observations are also consistent with the osteoimmunology framework of periodontitis, in which immune-cell–driven inflammatory signaling, RANKL-dependent osteoclastogenesis, and Th17/IL-17-associated responses cooperate to produce alveolar bone loss. In this context, the potential relevance of Lyn is not limited to inflammatory signaling alone, but may also extend to the coupling between immune dysregulation and bone resorption. ⁴³ In osteoclasts, SH3BP2 modulates RANKL signaling activity through its interaction with Syk. The study showed that loss of SH3BP2 markedly reduced alveolar bone resorption without affecting inflammation or osteoclast differentiation. Further experiments indicated that the SH3BP2–Syk axis regulates osteoclastic bone resorptive function rather than the differentiation process per se. Moreover, the Syk inhibitor GS9973 effectively decreased bone resorption when administered both before and after periodontitis induction, highlighting Syk as a potential therapeutic target. Collectively, these findings indirectly support a role for Lyn in the immunoregulatory processes underlying periodontitis.

Current evidence suggests that Lyn may be relevant to immune imbalance in periodontitis by shaping chemokine signaling, Th17-related inflammatory networks, and neutrophil function. Lyn may therefore be viewed as a context-dependent “molecular switch” within a hypothesis-generating framework. As illustrated in Figure 3, when Lyn activity is dysregulated, particularly when it is insufficient, a cascade may ensue: hyperactive B-cell responses → elevated Th17 → inadequate Treg restraint → excessive neutrophil trafficking → enhanced osteoclast activity, culminating in amplified chronic inflammation and accelerated bone loss that fuels periodontitis progression. Figure 3 presents a conceptual hypothesis rather than an established causal mechanism. Although the model requires further validation, previous bioinformatic observations showing upregulated Lyn expression in periodontitis tissues provide a rationale for further investigation of this hypothesis. The underlying molecular processes engage multiple signaling pathways closely tied to disease initiation and progression. Future work should define Lyn’s precise roles and regulatory network in periodontitis to inform prevention and therapeutic strategies.

Figure 3.

Conceptual hypothesis of the potential role of Lyn in periodontitis.

5. Immunopathologic parallels between periodontitis and autoimmune diseases

Periodontitis shares selected immunopathologic features with autoimmune diseases, although it should not be regarded simply as a localized autoimmune disorder. Their shared pathogenic mechanisms primarily encompass three aspects: Firstly, patients exhibit abnormal antibody responses, including elevated levels of antigen-specific antibodies and non-specific immunoglobulins such as IgG, which may target and attack self-tissues. Secondly, the inflammatory regulation mechanisms in periodontitis resemble those in autoimmune diseases, involving dysregulated inflammatory responses mediated by TLRs and the NLRP3 inflammasome. This parallels the pathological processes observed in conditions like RA. Finally, Lyn kinase demonstrates dual regulatory roles in both disease types. It can activate specific immune pathways, such as the Th17 pathway, while also suppressing others. In periodontitis, Lyn may participate in inflammatory regulation through pathways linked to immune activation and inhibitory feedback, but its mechanistic role remains hypothesis-generating rather than established.

The key differences between these two diseases lie in the distinct functions of Lyn within their respective signaling pathways (Table 1). In SLE, Lyn primarily regulates the Th1/Th2 balance, maintaining immune homeostasis by modulating pathways such as IL-17 and TGF-β. Conversely, in periodontitis, Lyn may influence the inflammatory response through pathways such as chemokine signaling (hsa04062), immune cell activation, and inflammation-related signaling pathways like NF-κB and MAPK. In this context, Lyn may be associated with the regulation of inflammatory mediators, although the direction and net effect of this regulation are likely to depend on cell type and signaling context. Pathologically, SLE is fundamentally an autoimmune response against self-antigens, with Lyn maintaining balance by regulating Th17 and Treg cell functions. In contrast, periodontitis is a multifactorial, non-specific inflammatory condition driven by factors such as IL-6, IL-1β, and TNF-α. Any proposed role of Lyn in periodontitis should therefore be interpreted within a dysbiosis-driven host–microbe inflammatory framework, rather than being directly equated with classic autoimmune disease mechanisms.

Table 1.

Selected immunopathologic parallels and distinctions between autoimmune diseases and periodontitis.

Mechanism	Systemic lupus erythematosus (SLE)	Periodontitis	Key references
Lyn Function	Dual Dysregulation: Activates Th17/Inhibits Treg	Positive Dominance: Promotes chemokine secretion	SLE: 17, 28 Periodontitis: 18
Core Pathway	IL-23/Th17 axis	Lyn-PTK2B-Crk/paxillin	SLE: 28 Periodontitis: 18
Inflammatory Outcome	Multi-organ autoimmune damage	Local bone resorption and tissue destruction	SLE: 21–23, 28 Periodontitis: 7–9, 42, 43

6. Therapeutic potential of Lyn for chronic periodontitis

6.1. Preclinical evidence

6.1.1. Pharmacologic inhibition of Lyn-related signaling

Dasatinib, a second-generation tyrosine kinase inhibitor, functions by inhibiting the activity of multiple tyrosine kinases, including BCR-ABL, SFKs (such as SRC, LCK, HCK, YES, and Lyn), KIT, and PDGFR, as well as DDR1 and DDR2. ⁴⁴ Compared to first-generation tyrosine kinase inhibitors like imatinib, dasatinib exhibits greater potency and a broader spectrum of targets. In a preclinical study by Kai Guo et al., ⁴⁴ the anti-inflammatory and joint-protective effects of dasatinib were evaluated using a CIA mouse model and fibroblast-like synoviocytes (FLS) derived from RA patients. The results demonstrated that dasatinib significantly alleviated arthritis symptoms and prevented joint destruction in CIA mice. It also inhibited the production of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6, while promoting the secretion of the anti-inflammatory cytokine IL-10. Moreover, dasatinib suppressed the migration and proliferation of FLS and induced apoptosis in these cells, alongside downregulating mRNA expression levels of MMP13, VEGF, FGF, and DKK1. These findings suggest that dasatinib holds potential for RA treatment through its multi-target effects. Considering Lyn’s immunoregulatory role in RA pathology, dasatinib, as an inhibitor of Lyn-related signaling, may indirectly modulate inflammatory and autoimmune responses. However, because dasatinib is not Lyn-specific and has not been validated as a targeted therapy in periodontitis, these observations should be interpreted as translational context rather than direct evidence of periodontal efficacy. In periodontitis, whether inhibition of Lyn-associated pathways would be beneficial remains to be determined in periodontal-specific models.

6.1.2. Pharmacologic activation of Lyn-related signaling

MLR-1023 is a novel insulin sensitizer. ⁴⁵ Ochman et al., ⁴⁶ through animal experiments inducing insulin deficiency and hyperglycemia in mice, explored the insulin receptor sensitizing effects of MLR-1023 and observed its rapid and sustained ability to improve blood glucose homeostasis in models of type 2 diabetes. The study found that MLR-1023 enhances the insulin receptor signaling pathway by activating Lyn kinase, resulting in rapid-onset and lasting hypoglycemic effects. There is a bidirectional relationship between type 2 diabetes and periodontitis: diabetic patients are more susceptible to developing periodontitis, and conversely, periodontitis can worsen glycemic control by exacerbating diabetic conditions. As a novel insulin sensitizer, MLR-1023 improves insulin sensitivity and blood glucose regulation, which may indirectly reduce the risk of periodontitis in diabetic individuals or lessen its impact on diabetes management. Furthermore, both periodontitis and diabetes are closely associated with chronic inflammation. Since MLR-1023 modulates the insulin signaling pathway through Lyn kinase activation, and Lyn kinase also plays roles in inflammation and immune responses, it is plausible that MLR-1023 might indirectly influence the pathological processes of periodontitis by modulating inflammation-related mechanisms. However, this possibility remains speculative, because current evidence is derived from metabolic disease models rather than periodontal-specific studies. Importantly, the apparent contrast between dasatinib and MLR-1023 does not necessarily indicate inconsistency; instead, it supports the view that the biologic consequences of Lyn modulation may depend on disease context, cell type, and the balance between activating and inhibitory signaling.

6.2. Translational implications of Lyn-related modulation in periodontitis

The dual regulatory functions of Lyn kinase in systemic autoimmune diseases (e.g., SLE and RA), mediating both immune activation and inhibitory feedback, offer an important paradigm for understanding its potential role in periodontitis. The present review suggests that Lyn may be relevant to immune imbalance in periodontitis, where dysregulated signaling could potentially influence inflammatory cell infiltration and bone destruction through pathways such as chemokine signaling. This proposed framework shares selected molecular features with autoimmune diseases, such as altered Th17/Treg-related immune balance. Previous transcriptomic and histologic observations, including upregulation of Lyn-related pathways in gingival tissues, provide a rationale for further investigation, but do not yet establish that the Lyn→PTK2B→Crk/Paxillin cascade is a key driver of periodontitis progression. Regarding translational applications, Lyn-related strategies may hold potential in three areas: Firstly, in diagnostics, measuring Lyn/PTK2B expression levels could serve as a molecular marker for disease activity. Secondly, therapeutically, approaches derived from autoimmune disease treatments could be adapted to block downstream chemokine networks involved in periodontitis. Thirdly, developing tissue-specific delivery systems (e.g., localized sustained-release formulations for gingival tissues) is crucial to minimize systemic immunosuppression. At present, however, these translational implications remain hypothesis-generating and require direct validation in periodontal models.

Future research should focus on elucidating the dynamic roles of Lyn in different clinical types of periodontitis, exploring its interactions with the oral microbiome, and identifying optimal intervention windows based on the activity cycle of Lyn. Such studies may help establish a stronger theoretical foundation for future immunomodulatory strategies in periodontitis, but the therapeutic relevance of Lyn should currently be regarded as promising yet still unvalidated.

7. Limitations of the study

This review has several limitations. First, it is a narrative review rather than a systematic review, and therefore the literature selection process may be influenced by the availability and interpretive emphasis of the authors. Second, direct evidence linking Lyn to periodontitis remains limited, and much of the current discussion relies on transcriptomic, bioinformatic, or cross-disease evidence together with mechanistic extrapolation from other inflammatory settings. Third, several proposed links—particularly those involving Th17/Treg balance, inflammasome-associated signaling, and osteoimmune bone resorption—should be interpreted as hypothesis-generating rather than causally established in periodontal lesions. Accordingly, the proposed framework requires direct validation in periodontal-specific cell, animal, and clinical studies.

8. Conclusion

Lyn is a biologically plausible but still incompletely defined immunoregulatory candidate in periodontitis. Current evidence supports a context-dependent role for Lyn in inflammatory signaling, immune imbalance, and bone-destructive processes, but direct periodontal proof remains limited. The main contribution of this review is to place Lyn within a periodontitis-centered framework that integrates dysbiosis-driven host responses, NF-κB- and IL-1β-related inflammation, Th17/Treg-associated imbalance, and osteoimmune bone resorption. At present, Lyn should be regarded not as an established mechanistic driver, but as a hypothesis-generating molecular node that warrants further investigation in periodontal-specific models.