Systemic lupus erythematosus (SLE) is a complex inflammatory autoimmune disease characterized by the interplay of genetic, immunological, and environmental factors (Akhil et al., 2023). The multi-system involvement of SLE results in a broad spectrum of clinical manifestations, often affecting the skin, joints, kidneys, cardiovascular, and respiratory systems (Fava and Petri, 2019; Ameer et al., 2022). In recent years, there has been growing attention to oral health complications in SLE patients, including temporomandibular joint dysfunction, tooth loss, and oral mucosal lesions (Aceves-Avila et al., 2013; Benli et al., 2021). Notably, the incidence of dental caries is significantly higher in SLE patients than in the general population, closely linked to reduced salivary secretion and alterations in the oral microbiome (Loyola Rodriguez et al., 2016). These oral health issues not only diminish the quality of life but also may exacerbate the systemic burden of the disease (Corrêa et al., 2018).

Periodontitis (PD) is a widespread chronic inflammatory disease, with a global prevalence estimated between 20% and 50% (Nazir, 2017). The pathophysiology of PD is primarily driven by bacterial infection, leading to persistent inflammation and the destruction of periodontal tissues (Sedghi et al., 2021). The progression of PD includes gingival inflammation, formation of periodontal pockets, bone resorption, and eventual tooth loss (Papapanou et al., 2018; Tonetti et al., 2018). PD is closely associated with several systemic diseases, including cardiovascular diseases, diabetes, rheumatoid arthritis, and SLE (Rutter-Locher et al., 2017; Baima et al., 2022; Kobayashi and Bartold, 2023). Among these, the relationship between SLE and PD has received particular attention. Epidemiological studies indicate that SLE patients are at a significantly increased risk of developing PD (Hussain et al., 2022). Clinical studies further reveal a bidirectional influence between SLE and PD. One study demonstrated that periodontal treatment in SLE patients significantly reduced disease activity, suggesting that effective management of periodontitis may positively impact the systemic condition of SLE (Fabbri et al., 2014).

Genetic studies reveal that SLE and PD share specific pathogenic genes and signaling pathways. For instance, polymorphisms in the Fcγ receptor gene play a crucial role in both diseases (Kobayashi et al., 2003; Kobayashi et al., 2007). Certain Fcγ receptor alleles in SLE patients are associated with more severe periodontal destruction, highlighting the importance of genetic susceptibility in the shared pathogenesis of these two diseases (Kobayashi et al., 2003). Additionally, Toll-like receptor (TLR) signaling pathways are abnormally activated in both SLE and PD, further suggesting an immunopathological link between them (Marques et al., 2016; Wallet et al., 2018). From a microbiological standpoint, immune dysfunction in SLE patients leads to an imbalance in the oral microbiome, facilitating the overgrowth of periodontal pathogens (Bagavant et al., 2018; Pessoa et al., 2019). Specifically, Porphyromonas gingivalis is believed to play a central role in the pathogenesis of both PD and SLE. Studies have shown that the abundance of this pathogen is significantly higher in the oral cavities of SLE patients and is correlated with the severity of periodontal tissue destruction (Graves et al., 2019). Furthermore, elevated levels of pro-inflammatory cytokines (such as TNF-α and IL-6) in SLE patients exacerbate periodontal inflammation, resulting in more severe damage to periodontal tissues (Martínez-García and Hernández-Lemus, 2021). The existing evidence strongly supports a close biological connection between SLE and PD. Further exploration of the shared mechanisms underlying these two diseases could not only enhance the understanding of their pathogenesis but also provide novel therapeutic approaches for their combined management.

In this study, we comprehensively analyzed gene expression datasets for both SLE and PD obtained from the GEO database. The identification of shared genes between SLE and PD was achieved through the detection of DEGs and WGCNA of the dataset. Subsequently, we conducted GO and KEGG analyses on the identified genes, followed by the construction of PPI networks. To substantiate our findings, we employed machine learning algorithms, specifically RF and LASSO, to ascertain common core genes possessing the utmost diagnostic significance in both afflictions. Finally, we conducted immune cell infiltration analysis to examine the differences in immune cell composition between SLE and PD patients, and assessed whether these differences correlate with the expression levels of shared core genes. Through this comprehensive bioinformatics analysis, we aim to offer new insights and perspectives for the clinical management of SLE concurrent with PD by enhancing our understanding of the biological connections between SLE and PD.

SLE is a multifaceted autoimmune disorder, and its pathophysiological mechanisms remain incompletely understood (Hoi et al., 2024). PD is an infectious disease marked by an imbalance of microbial flora in periodontal tissues, resulting in chronic inflammation and gradual deterioration of periodontal supporting tissues. Recent studies indicate that individuals with SLE face an elevated risk of developing PD, with a risk approximately 1.76–1.78 times higher than the general population (Rutter-Locher et al., 2017; Bolstad et al., 2022). Furthermore, various biological hypotheses propose comparable pathophysiological mechanisms between these conditions, encompassing shared genetic, microbiological, immunological, and environmental risk factors (Sojod et al., 2021). Nevertheless, research investigating the genetic link between SLE and PD remains limited. Thus, the discovery of biomarkers and underlying molecular mechanisms pertaining to both SLE and PD via bioinformatics analysis holds significant clinical relevance.

This study utilized comprehensive bioinformatics analysis employing machine learning algorithms. Initially, we analyzed DEGs from the GSE72326 and GSE16134 datasets. Subsequently, DEGs were integrated with genes in the WGCNA module, leading to the identification of 50 candidate genes shared across the datasets. These 50 common candidate genes underwent enrichment analysis, revealing significant associations with the PI3K-Akt signaling pathway and B-cell receptor signaling pathway. Afterwards, we identified five core genes (CD19, CD79A, CD163, GZMK, IL7R) through PPI network analysis. To enhance the screening of diagnostic genes, machine learning algorithms were utilized to analyze overlapping genes. Ultimately, we identified 11 shared hub genes and validated them using ROC curves.

Our findings indicate a significant involvement of the PI3K-Akt signaling pathway in both the onset and progression of SLE and PD. It is crucial in regulating cell proliferation, differentiation, B cell and T cell receptor signaling, as well as macrophage polarization (Nestle et al., 2005; Dong et al., 2019; Linton et al., 2019; Chen et al., 2020). Similarly, the pathogenesis of SLE involves abnormal B cell activation, T cell dysregulation, and polarization of M1 macrophages (Rawlings et al., 2017; Ma et al., 2019; Tenbrock and Rauen, 2022). B-cell activating receptors such as BCR, CD40, and TLRs are all linked to the PI3K signaling pathway (Okkenhaug and Vanhaesebroeck, 2003; Donahue and Fruman, 2004; Hodson and Turner, 2009). In macrophages, the PI3K signaling pathway regulates the polarization state by modulating metabolic and inflammatory responses. Activation of this pathway suppresses M1-type macrophage polarization and enhances M2-type macrophage polarization (Long et al., 2021; Acosta-Martinez and Cabail, 2022). In clinical practice, focusing on the PI3K-Akt signaling pathway has also shown favorable therapeutic effects in patients with SLE (Shen et al., 2022). For instance, azithromycin can activate M2 macrophages via this pathway, thus reducing inflammation and improving the condition of SLE (Wang et al., 2018). The PI3K-Akt pathway plays a pivotal role in immune imbalance, inflammation regulation, and the maintenance of periodontal tissue homeostasis in PD. Studies have demonstrated that FBLN3 is upregulated in PD tissues, promoting M1 macrophage polarization via the EGFR/PI3K/AKT signaling pathway. This activation enhances the pro-inflammatory response and exacerbates periodontal tissue damage (Mu et al., 2024). Furthermore, PI3K-Akt modulates macrophage metabolism through HIF-1α-mediated glycolysis, sustaining M1 macrophage activation while suppressing M2 macrophage transition within the PD immune microenvironment (Zeng et al., 2024). Beyond immune cell polarization, PI3K-Akt plays a central role in the trained immunity of gingival fibroblasts (GFs). Porphyromonas gingivalis-derived lipopolysaccharide (LPS) has been shown to induce a trained immune response in GFs via PI3K/AKT pathway activation, leading to increased IL-6 and TNF-α secretion and sustaining inflammation through epigenetic modifications (Liu et al., 2024). Moreover, PI3K-Akt regulates osteoclast function, thereby influencing alveolar bone resorption and regeneration. Studies have identified the PI3K/AKT/GSK-3β signaling pathway as a key regulator of LPS-induced osteoclast activation and alveolar bone loss. Inhibiting this pathway has been found to reduce bone resorption, mitigate inflammation, and improve inflammatory bone loss (Lv et al., 2025). Additionally, PI3K-Akt may alleviate oxidative stress by enhancing cellular antioxidant capacity, thus contributing to the preservation of periodontal tissue homeostasis (Fu et al., 2023). In conclusion, the dysregulated activation of PI3K-Akt in PD not only influences immune cell polarization but also perpetuates inflammation and promotes alveolar bone loss by modulating trained immunity and bone metabolism. Given its critical role in both PD and immune dysregulation in SLE, PI3K-Akt represents a promising therapeutic target. Our findings further corroborate its pathological significance in PD and provide supporting evidence for its potential in targeted therapy.

In our research findings, hub genes are equally crucial for the clinical significance of both SLE and PD. We have identified eight key hub genes as diagnostic biomarkers (PLEKHA1, CEACAM1, TNFAIP6, TCN2, GLDC, GNG7, LY96, VCAN). Based on the current research status, we have focused on VCAN and LY96. While direct interactions between VCAN, LY96, and SLE remain undisclosed in current studies, their potential associations with SLE warrant attention. The VCAN gene encodes the Versican protein, a binding protein crucial for tissue morphogenesis and extracellular matrix formation, which is integral to tissue inflammation in response to infection and tissue damage (Wight et al., 2014). Versican exerts pro-inflammatory effects by modulating the adhesion of myeloid and lymphoid cells, particularly T lymphocytes and monocytes, which are regulated by multifunctional proteoglycans (Gill et al., 2010; Potter-Perigo et al., 2010; Evanko et al., 2012). Moreover, Versican interacts with inflammatory cells through two pathways: indirect binding to hyaluronic acid, and direct interaction with receptors like CD44, P-selectin glycoprotein ligand-1 (PSGL-1), and toll-like receptors (TLR), found on both immune and non-immune cell surfaces. These engagements activate signaling cascades that stimulate the synthesis and secretion of inflammatory cytokines, such as TNF-α, IL-6, and NF-κB (Wight et al., 2020). Notably, CD44 stands out as a significant therapeutic target in SLE, as it governs disease progression by modulating B cell activation and proliferation (Yi et al., 2023). Reduced expression of PSGL-1 in neutrophils of active SLE patients may lead to excessive release of Neutrophil Extracellular Traps (NETs). This excessive NETs release may exacerbate the disease by triggering an immune response through their DNA content, worsening inflammation and autoimmune reactions, thereby driving disease progression (Muñoz-Callejas et al., 2023). Additionally, the significance of VCAN in PD warrants attention. Expression levels of TLR4 are markedly elevated in PD patients, positively correlating with disease severity (Promsudthi et al., 2014). LY96, also known as myeloid differentiation factor-2 (MD-2), plays a crucial role in the innate immune response by serving as a ligand receptor tightly bound to (TLR4) (Wu et al., 2022b). TLR4 is involved in the pathogenesis of SLE by regulating the inflammatory response and promoting autoantibody production. Inhibiting TLR4 can alleviate inflammation and ameliorate kidney damage (Ma et al., 2018). Furthermore, TLR4 is implicated in immune response regulation during SLE pathogenesis through diverse pathways, encompassing immune cell activation, autophagy modulation, and interaction with type I IFN signaling pathway (Wu et al., 2022a). Thus, LY96 serves as the primary mediator in linking TLR4 with the association between SLE and PD. In summary, our findings suggest that VCAN and LY96 could represent novel therapeutic targets for both SLE and PD, thereby providing a robust groundwork for elucidating their underlying mechanisms in subsequent studies. Another important finding is that GNG7 demonstrates distinct correlations in SLE and PD, potentially influenced by variations in the immune microenvironment, signaling pathway regulation, and data sources. SLE is typically characterized by widespread immune dysregulation, whereas PD manifests as localized chronic inflammation. These contrasting immune landscapes may result in differences in the regulatory mechanisms of GNG7-mediated signaling pathways in the two diseases. Nevertheless, since CIBERSORTx immune infiltration analysis is applicable to various tissue environments, its findings remain biologically relevant to immune regulation, underscoring the need for further investigation into the underlying mechanisms. Future studies should employ single-cell transcriptomic analysis to elucidate the cell-type-specific roles of GNG7 and validate its regulatory mechanisms in immune cell function through in vitro experiments.

Additionally, alterations in immune cell populations appear to be pivotal in the interplay between SLE and PD. Our findings indicate that various immune cells are upregulated in SLE, including neutrophils and monocytes, while their expression is less pronounced in PD. Activated neutrophils are capable of generating a multitude of cytokines and chemokines, potentially leading to dysregulated functions of B and T cells, thereby exacerbating SLE pathogenesis (Smith and Kaplan, 2015). Aberrant monocyte activation in SLE stimulates dendritic cells and T/B cells through extensive interferon-alpha (IFN-α) and other inflammatory mediator secretion, culminating in autoantibody generation and tissue inflammation (Hirose et al., 2019). Conversely, In PD, substantial increases were observed in plasma cells, γδ T cells, M0 macrophages, and resting NK cells. The involvement of plasma cells is pivotal in the pathogenesis of PD, contributing to antibody production, immune response regulation, and inflammation-induced bone loss (Zouali, 2017). γδ T cells, abundant in epithelial tissues such as gingival tissues, may exert their functions in PD through diverse mechanisms, including immune surveillance, maintenance of immune homeostasis, and modulation of epithelial tissue repair processes (Figueredo et al., 2019). Notably, despite variations in the immune cell profiles upregulated in SLE and PD, there exists a close interconnection among these cells. Specifically, neutrophils support the survival and function of plasma cells by releasing B cell activating factor (BAFF) and directly interacting with them, thereby augmenting the immune response through enhanced plasma cell survival and antibody production (Zhao et al., 2019; Sabat et al., 2023). Additionally, γδ T cells modulate neutrophil activation and polarization by secreting IL-17, and encourage neutrophils to engage in suppressing T cell immune responses (Coffelt et al., 2015). In monocytes and γδ T cells, the v-γ9vδ2 + T cell subset within γδ T cells can activate monocytes by secreting inflammatory molecules like IFN-γ and TNF-α, inducing their adhesion and aggregation, and enhancing monocyte survival. Conversely, monocytes can induce the activation of Vγ9Vδ2+ T cells by accumulating and presenting phosphate antigens, thereby establishing a bidirectional regulatory interaction between these cell types (Chan et al., 2022). Monocytes critically contribute to the development and function of plasma cells by secreting factors vital for plasma cell survival and development, and by facilitating plasma cell proliferation through intercellular interactions (Mohr et al., 2009). The results of immune infiltration underscore the indispensable role of these immune cells in both SLE and PD.

In summary, our study clarifies the common molecular mechanisms underlying SLE and PD. We identified eight candidate genes (PLEKHA1, CEACAM1, TNFAIP6, TCN2, GLDC, GNG7, LY96, VCAN) as potential biomarkers for diagnosis. Analysis of immune infiltration demonstrated their intimate association with immune cells. Moreover, the PI3K-AKT signaling pathway likely plays a significant role in the interaction between SLE and PD. These discoveries establish a molecular basis for further investigating the relationship between SLE and PD.