Chronic hepatitis B (CHB) caused by the hepatitis B virus (HBV) is a liver disease (1). HBV is one of the most common human pathogens and leads to serious public health problems. According to the World Health Organization’s (WHO) report in 2024, approximately 254 million people worldwide suffer from chronic hepatitis B (CHB), with an annual increase of approximately 1.2 million new infections (2). Active HBV replication can lead to immune liver injury, cirrhosis, hepatocellular carcinoma, and even liver failure (3). The tolerance effects of the hepatic environment and continued exposure of T cells to high antigen loads result in the suppression of T cell function in chronic HBV infection. This leads to the induction of HBV-specific T cell responses that are prompt and efficient in acute self-limiting infections but profoundly depleted in CHB (4).

Tuberculosis (TB) represents a significant global public health concern, caused by Mycobacterium tuberculosis (Mtb), with over 80% of cases and deaths occurring in low-income and middle-income countries (5). Tuberculosis can affect individuals of any age and gender, with a particularly high prevalence among adult males, but by 2022, only approximately two-fifths of individuals with drug-resistant tuberculosis will have access to treatment (5, 6). Tuberculosis is primarily a lung disease, with pulmonary tuberculosis accounting for 70% of cases. However, 30% of patients will also develop extrapulmonary disease, with the bacillus spreading to other organs such as the lymph nodes, bones, and meninges (7). The increasing prevalence of drug-resistant Mtb is attributable to a number of factors, including inappropriate use of TB medications, incorrect prescription by healthcare providers, poor-quality medications, and premature cessation of treatment (8).

The relationship between HBV and TB is not yet clear, but some studies have revealed some potential links between the two in clinical manifestations, immune response and drug interaction. In the setting of HBV infection, the development of TB is associated with a poor prognosis and poor response to treatment in patients, with adverse outcomes occurring six times more often than in patients infected only with TB and two times more often than in those experiencing liver failure, largely due to the effects of systemic immunity (8, 9). Individuals infected with HBV are at an elevated risk of developing latent tuberculosis, and vice versa (10). The likelihood of mixed infections is highest among those born in countries with a high prevalence of both diseases, particularly among Asians (10). It is established that cirrhosis due to CHB infection represents a risk factor for extrapulmonary TB and there are numerous reports of specific manifestations of TB in patients with cirrhosis and TB (11). In chronic HBV infection, HBV inhibits the ability of natural killer (NK) cells to produce interferon gamma (IFN-γ) by mediating an environment of high levels of immunosuppressive cytokines, such as interleukin-10 (IL-10), secreted by CD4⁺ CD25⁺ regulatory T cells (Tregs) (12, 13). IFN-γ production is an important effector mechanism of CD4⁺ T cell-mediated protective immunity in patients with TB (14, 15). Concurrently, TB diminishes antigen presentation by immune cells in the liver by inducing apoptosis of immune cells, particularly CD4⁺ T cells, thereby elevating the likelihood of HBV infection (16, 17). In TB patients with HBV infection and, liver dysfunction is exacerbated by the hepatotoxicity of anti-TB drugs and immune hepatic injury due to HBV replication (8). It has been asserted that the incidence of drug-induced liver injury (DILI) in TB patients with HBV infection is twice as high as the incidence in patients with TB alone (18). The results of these studies indicate a significant interaction between HBV infection and TB.

This study used the Gene Expression Omnibus (GEO) database (GSE83148 and GSE126614), systematically identifying the differentially expressed genes (DEGs) of the two diseases and focusing on their overlap. Based on common genes, in-depth pathway and gene function annotation analyses were performed. To narrow the focus of candidate genes, we constructed a protein–protein interaction (PPI) network of shared genes and identified hub genes in the network. Hub genes were used to explore the associated transcription factor (TF) regulatory network and predict potential therapeutic agents. Finally, we analyzed the association of these interacting genes with multiple disease contexts. Figure 1 illustrates the workflow of the analysis. This study provides insights into the molecular commonalities and response mechanisms of HBV and TB infection, intending to uncover new drug candidates and precise targets for HBV infection therapy to optimize patient prognosis.

The morbidity and mortality associated with liver diseases resulting from HBV and TB infection are considerable (38, 39). Concurrently, the aetiology of both conditions is linked to the body’s immune response (3, 40). Conversely, some studies have indicated that the chronicity of both HBV and TB infection are primarily attributable to the attenuation of the host’s immune response, the emergence of immune tolerance, and the mutation of viral molecules and the secretion of related molecules, which facilitate evasion of the body’s immune response (3, 38, 40, 41). To date, no drug has been found to be effective in preventing liver damage caused by TB drugs in HBV patients infected with TB (42). Therefore, we used bioinformatics methods to investigate the link between HBV infection and TB to find some potential drugs.

The application of enrichment analysis to gene ontologies and pathways enables the elucidation of the function and regulatory mechanisms of genes in diverse physiological states. In this study, we initially identified 35 common DEGs through differential analysis of gene expression abundance in transcriptional profiles and Venn diagram analysis. This suggests a certain degree of correlation and resemblance between HBV infection and TB in pathogenesis. Subsequently, we performed a functional enrichment analysis on the common DEGs. The results of this analysis demonstrated that these common DEGs were primarily involved in immune-related pathways and cellular metabolic regulation. The central role of aberrant activation of immune checkpoints has been demonstrated in HBV and TB infection. HBV has been observed to upregulate programmed cell death (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4) and T cell immunoglobulin domain and mucin domain-3 (TIM-3), leading to T cell depletion (43–45). Concurrently, TB has been observed to impede T cell functionality through the PD-1/IL-10 axis (46–48). It has been demonstrated that both HBV and Mtb are capable of evading the host immune system by disrupting IFN signaling. Specifically, HBV has been shown to inhibit IFN production via non-structural proteins, while Mtb has been observed to induce a deleterious IFN response and to inhibit macrophage activation, thereby weakening the intrinsic immunity of the hepatocyte and IFN-γ-mediated antimicrobial function (4, 49, 50). Studies have shown that both HBV and TB exhibit common cellular metabolic regulation in their pathogenesis (51, 52). It has been demonstrated that Mtb subverts host immunity by hijacking glycolysis as evidenced by the Warburg effect and lipid metabolism. This results in the disruption of mitochondrial function and the inhibition of pro-inflammatory cytokines, such as IL-1β, to evade immune clearance (53, 54). And HBV has been observed to exert a comparable effect on the metabolic networks of the host, thereby promoting viral replication through glycolysis, lipid accumulation, and mitochondrial dysfunction (55–57).

Shared DEGs were used to construct a PPI network in which hub genes represent key regulators in the pathogenic processes of both HBV and TB. The four hub genes identified—CCL2, CD69, EGR2, and CCL20—are functionally associated with immune modulation and inflammatory responses. CCL2 is a well-known inflammatory chemokine that facilitates the migration of monocytes, memory T cells, macrophages, and natural killer (NK) cells to inflamed tissues (58). In HBV infection, the virus manipulates inflammatory signaling to support persistent replication and establish an immunosuppressive microenvironment. HBV has been shown to upregulate CCL2 expression through the activation of the TGF-β/miR-34a/CCL2 axis and by inducing mutations in the CCL2 promoter via activation of the cytidine deaminase family (59, 60). This promotes the recruitment of tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), thereby dampening cytotoxic CD8⁺ T cell responses. In TB, elevated CCL2 expression is associated with disease severity and is thought to contribute to leukocyte recruitment and granuloma formation during pulmonary infection (61). CD69, a C-type lectin receptor, is one of the earliest markers of lymphocyte activation (62). In chronic HBV infection, CD69 expression is often downregulated, correlating with reduced T cell activation and antiviral function, which can be partially restored with antiviral therapy (63). In the context of TB, persistent CD69 expression on Mtb-stimulated T cells has been linked to impaired host defense and disease progression, potentially due to sustained immune activation and exhaustion (64). EGR2 is a transcription factor involved in the regulation of immune cell development and function. It plays a critical role in chronic HBV infection by mediating immune evasion, particularly through the regulation of Fas ligand (FasL) expression in hepatocytes in response to HBx protein (65). In TB, EGR2 is upregulated via the IFN-I-IFNGR1 signaling axis, contributing to the suppression of macrophage activation and increasing susceptibility to Mtb infection (66, 67). CCL20, another chemokine identified among the hub genes, exerts chemotactic effects on lymphocytes and dendritic cells through its receptor CCR6 (68). In HBV, CCL20⁺ Th17 cells are elevated and contribute to liver inflammation and fibrosis (69). In TB, upregulation of CCL20 has been observed in response to Mtb antigens, mediated by TNF-α/IFN-γ and the MAPK/NF-κB pathways, suggesting a role in immune cell recruitment during active infection (70). Although these findings provide plausible mechanistic insights, further experimental validation through in vitro or in vivo studies is necessary to confirm the specific roles of these genes in the co-infection context.

To better understand the pathological basis of these disease states, transcription factors that act as upstream regulators of these pivotal genes have also been identified, such as NFKB1 and FOXC1. NFKB1 is a repressor of inflammation, ageing, and cancer (71). NF-κB can inhibit HBV replication via myeloid differentiation primary response protein 88 (MyD88), a key molecule in the innate immune response signaling cascade (72). Active inflammation in response to NF-κB expression may play a key role in promoting immune clearance of HBV (73). NFKB1 is up-regulated during TB infection, and it controls the transcription of genes involved in both the pro-inflammatory and anti-apoptotic responses. Mtb inhibits macrophage apoptosis early in the course of infection by upregulating the NF-KB signaling pathway (39). The FOXC1 transcription factor is involved in normal embryonic development and regulates organ function (74). In HBV infection, HBV X protein significantly upregulates FOXC1 expression and transactivates its promoter activity through the Extracellular Signal-Regulated Kinase/CAMP Response Element Binding Protein (ERK/CREB) signaling pathway (75). For TB, FOXC1 is critical for mesenchymal lineage specification and organ development (76). Mesenchymal stem cells (MSCs), as a new class of phagocytes and immune cells, not only provide drug-resistant and immune-privileged ecological niches for dormant Mtb, but also have the ability to limit Mtb growth to a certain extent, which may be involved in the development of TB (77). Thus, FOXC1 could indirectly influence TB development through the regulation of MSCs. Although many previous studies have suggested that these TFs may have potential therapeutic effects, the results of these analyses require further experiments to confirm their validity and authenticity.

A series of candidate drugs targeting the DEGs were identified using the DSigDB database, including etoposide, 8-azaguanine, menaquinone, emetine, and N-acetyl-L-cysteine. Although these agents are not conventional first-line therapies for TB or HBV infection, accumulating evidence supports their potential antiviral or antibacterial effects. Etoposide, a topoisomerase II inhibitor primarily used in cancer therapy (78), has shown promise in managing severe virus-associated immune responses. For instance, etoposide was effective in a patient with virus-associated hemophagocytic syndrome (VAHS) secondary to HBV who failed to respond to standard immunosuppressive treatments (79). Moreover, etoposide combined with trichostatin A (a histone deacetylase inhibitor) overcame chemotherapy resistance in HBV-related hepatocellular carcinoma (HCC) cells via ERK inhibition and p53 activation (80). Etoposide has also been applied in TB-associated hemophagocytic lymphohistiocytosis (HLH) unresponsive to conventional anti-TB therapy (81), and recent studies indicate its ability to inhibit influenza virus replication by promoting PA subunit degradation (79). Clinical trials are currently evaluating etoposide’s use in managing COVID-19-induced hyperinflammation (80), suggesting a broader antiviral potential. 8-azaguanine, an immunomodulatory purine analog, has been shown to enhance natural killer (NK) cell cytotoxicity and exhibits antitumor and potential antiviral properties (82). It may exert its antibacterial effects through oxidative stress-related mechanisms, particularly in thiol-deficient bacteria (83). Menaquinone (vitamin K2), beyond its cardiovascular benefits (84), has gained attention in infectious disease research. Derivatives such as selenium-substituted menaquinones demonstrated strong anti-mycobacterial activity and the potential to overcome multidrug resistance in TB (85). Menaquinone biosynthesis enzymes, such as MenJ, are critical for mycobacterial survival in host cells, highlighting them as promising drug targets (86). Additionally, menaquinone has been implicated in preventing HBV progression to HCC by modulating apoptosis pathways (87, 88). Emetine, a natural alkaloid, inhibits ribosomal and mitochondrial protein synthesis and interferes with DNA/RNA activity (89, 90). It reduces cytokine production and demonstrates direct inhibitory effects on intracellular Mycobacterium tuberculosis by mimicking cytotoxic CD8⁺ T-cell responses (89, 91). N-acetyl-L-cysteine is a mucolytic and antioxidant compound widely used in respiratory and hepatic conditions. In vitro, NAC significantly reduced HBV DNA levels (92), and clinical studies have shown its benefits in HBV-related acute-on-chronic liver failure through antioxidant and anti-inflammatory effects (93). In TB, NAC limits infection by modulating host oxidative responses and inhibiting IL-6 production via MAPK/NF-κB signaling (94, 95). While these drugs exhibit promising antiviral or antibacterial properties, it is crucial to address their potential toxicity and tolerability, especially when used in combination therapy. Strategies to improve safety include dose optimization, close monitoring of immune and organ function, and combining agents such as immunomodulators or antioxidants (96, 97). Nevertheless, these approaches require further in vivo and in vitro validation to confirm efficacy and safety. Therefore, our findings should be interpreted as preliminary hypotheses, offering direction for future translational research on repurposing these compounds for HBV and TB treatment.

This research fills a critical gap in understanding the shared molecular mechanisms between HBV and TB, particularly by identifying common differentially expressed genes, enriched pathways, and potential therapeutic targets. While previous studies have largely focused on the immune response induced by a single pathogen, our study provides a systematic bioinformatics analysis of transcriptomic data from both diseases, offering a comprehensive view of their overlapping molecular signatures (38, 40). The hub genes identified in this study—such as CCL2, CD69, EGR2, and CCL20—may serve as candidate biomarkers indicating shared inflammatory or immune regulatory processes in HBV and TB (62, 98). For example, CCL2 and CCL20 are critical mediators of inflammatory cell chemotaxis, and EGR2 is involved in immune regulation and apoptosis (99). Targeting these genes may offer a rational approach for designing anti-inflammatory or immunomodulatory therapies relevant to both diseases (78). Furthermore, the drug-gene interaction analysis revealed several potential therapeutic compounds that may act on these shared targets. These findings not only offer new directions for drug repurposing and development, but also help bridge mechanistic insights into clinical applications by identifying drugs that may benefit patients with overlapping inflammatory or immune profiles across HBV and TB infections.

The identification of these genes provides valuable insights into potential therapeutic targets for both HBV infection and TB. However, several limitations should be acknowledged. First, the study relies on publicly available transcriptomic datasets that lack comprehensive clinical information, which may limit the interpretation of findings in a real-world clinical context. Second, our approach may have overlooked other important genes or signaling pathways not captured by the selected datasets or analytical criteria. Third, the absence of experimental validation using cellular or animal models limits the ability to confirm the functional roles of the identified targets. Additionally, potential methodological biases inherent in computational analyses may affect the reproducibility of results. To address these limitations, future studies will focus on incorporating multi-omics data, such as proteomics, metabolomics, and epigenetic profiles, to provide a more comprehensive view of the underlying molecular mechanisms. Experimental validation using in vitro and in vivo models will be performed to assess the biological functions and therapeutic potential of the identified targets. Moreover, efforts will be made to collect and integrate detailed patient clinical data to enable correlation analyses between gene expression changes and clinical outcomes, and to facilitate the identification of prognostic biomarkers with translational value.

In order to gain insight into the link between HBV infection and TB, we employed Bioinformatics and Systems Biology to identify common pathways and chemical biomarkers for HBV and TB infection. A total of 35 common DEGs for HBV and TB infection were identified through bioinformatics tools. GO and signaling pathway enrichment analysis revealed significant enrichment in immune-related pathways. Furthermore, the top four pivotal genes including CCL2, CD69, EGR2 and CCL20 were extracted through a PPI analysis of the DEGs, which may serve as biomarkers for HBV infection and TB treatment. We also investigated the relationship between genes and TFs like NFKB1 and FOXC1 to gain insight into potential therapeutic advances for both diseases. In addition, we have proposed a number of potential drugs, etoposide, 8-azaguanine, menaquinone, emetine and N-acetyl-L-cysteine, for the treatment of HBV infection and TB. The implications for potential new drugs of this study open up new possibilities for the treatment of HBV and TB.