Chronic hepatitis B (CHB) infection poses a significant global health challenge affecting the health and well-being of millions of people (1). Hepatitis B Virus (HBV) is a partially double-stranded DNA virus with a sophisticated life cycle that can persist by forming covalently closed circular DNA (cccDNA) within the host cell nucleus. The structure of HBV comprises a lipid envelope, with its surface characterized by three types of surface proteins, namely small (S), medium (M), and large (L), collectively referred to as HBsAg in serology. Additionally, there is an internal core-shell enveloping the core particles, known as the hepatitis B core antigen (HBcAg) in serology. The outer membrane forms an icosahedral shell composed of 120 core protein dimers (2–5). cccDNA plays a crucial role in the subgenomic RNA mediated by host RNA polymerase II, encompassing the surface protein HBx and two RNA templates exceeding the genomic length, namely pregenomic (pg) RNA and precore RNA. These two types of RNA exert significant regulatory functions, leading to the generation of the precore protein precursor, ultimately resulting in the secretion of hepatitis B e antigen (HBeAg) (6). Sustained HBV infection has the potential to induce diverse levels of liver impairment, culminating in progression to chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) (7, 8). According to the World Health Organization (WHO), approximately 300 million individuals worldwide are afflicted with chronic HBV infection, and nearly one million succumb annually to complications directly linked to HBV infection (9).

The risk of developing CHB infection depends on the age at exposure, with infants and children being mostly symptom-free. Approximately 95% of newborns, 20–30% of children (1-5 years old), and < 5% of adults fail to clear the virus after six months (10). During CHB infection, the virus remains in the body for a long period. This can lead to severe liver damage, such as cirrhosis and liver cancer, with significant repercussions for affected individuals, their families, and society at large (11–13). Although antiviral drugs can reduce the viral load in patients with hepatitis B, a complete cure remains difficult to achieve (6). Therefore, scientists are attempting to understand the mechanisms underlying this disease more thoroughly and promptly.

HBV infection can cause liver damage and chronic diseases; however, the virus is not cytotoxic. The immune system plays a key role in controlling viral replication and liver injury (14–16). Patients who achieve HBeAg seroconversion spontaneously or after antiviral therapy show improved immune function (17, 18). This implies that combining immunotherapy with antiviral treatment may increase the likelihood of viral elimination (19–22). The immune response to HBV infection is complex and variable. Some studies have reported that immune activation leads to reduced HBV DNA levels and HBeAg seroconversion, indicating effective clearance of infected hepatocytes (23). Other studies have reported that the reduction in HBV DNA levels is only temporary, suggesting ineffective clearance (24). Therefore, the host immune response is a critical factor in determining the outcome of HBV infection (25). The mechanisms by which HBV modulates the hepatic immune microenvironment to promote chronic infection are not fully understood.

Within the liver, there is a complex interplay among parenchymal (primarily hepatocytes), non-parenchymal, and recruited immune cells, collectively forming the hepatic immune microenvironment, which includes cellular components, secreted cytokines, and extracellular matrix components (26). One of the most intriguing features of the liver as a remarkable immune organ is its propensity to induce tolerance rather than immunity upon encountering foreign antigens (27). Specialized antigen-presenting cells in the liver, such as Kupffer cells and liver sinusoidal endothelial cells, are characterized by well-induced tolerance owing to their insufficient co-stimulatory signal transmission and tendency to produce immunosuppressive molecules, resulting in the establishment of an inherent hepatic tolerogenic microenvironment in a steady state (28). The nature of immune responses within the liver is intricately shaped by the level of inflammation. In cases of chronic or low-grade inflammation, where an immunosuppressive microenvironment prevails, the liver can serve as a “graveyard” for effector cells (29) or as a “school” for educating regulatory cells (30). These processes can lead to clonal deletion (31, 32) or suppression of antigen-specific T cells (33–35), which constitute the primary mechanisms underlying liver-induced antigen-specific tolerance. During CHB infection, HBV replication within hepatocytes goes unnoticed by the intracellular innate immune system, resulting in a tolerogenic hepatic microenvironment. This gradually leads to the alteration and deletion of the functional capacities of HBV-specific B and T cells, enabling the establishment of intractable persistent (chronic) HBV infection (36). However, how these mechanisms coordinate to sustain the tolerance of the hepatic microenvironment while the virus persists in the liver remains largely unknown (37). According to recent research in the relevant field, immunometabolism and epigenetic reprogramming have emerged as pivotal factors linking hepatocytes and immune cells within the hepatic immune microenvironment, as elaborated in the subsequent sections.

The immune system is intricately linked to metabolic functions in a manner that has not been previously recognized. This unconventional mode of thinking has been described in a novel field known as immunometabolism (38, 39). Immunometabolism encompasses a series of processes involving the energy metabolism of immune cells in response to pathogens, accumulation of metabolic products, and regulatory activity of metabolic enzymes (40). Reports of cellular metabolism being hijacked by viruses have a history spanning over half a century; however, the mechanisms and consequences of virus-induced metabolic reprogramming have only begun to be extensively studied over the past decade (41). Following internalization by glucose transporters, glucose molecules enter distinct metabolic pathways, including glycolysis and the pentose phosphate pathway (42, 43), each of which serves specific functions and purposes. To some extent, these changes influence the functionality of immune cells, thereby affecting the effectiveness of antiviral immune responses.

In addition to immunometabolism, epigenetic modifications play crucial roles in regulating gene expression (44, 45). Simultaneously, there is a vital interplay between metabolism and the epigenetic modification in immune regulation that disrupts the functionality and response patterns of immune cells (46, 47). The interaction between metabolism and epigenetics led to a new research field known as metabolic epigenomics (48). Recently emphasized metabolites such as lactate (49, 50), and a newly discovered epigenetic modification, lactylation (51), serve as noteworthy representatives. This combination also includes acetyl-CoA and histone acetylation (52, 53), S-adenosylmethionine and histone methylation (54, 55), as well as NAD⁺ and the Sirtuin family (56). These intricate interactive relationships play a pivotal role in the dynamic balance between immune responses and sustained viral infections.

During CHB infection, significant alterations occur in host immune metabolism, including glucose and lipid metabolism (57, 58). For instance, during HBV infection, cells involved in pathological responses, such as immune cells and hepatocytes, enhance utilization and glucose uptake to meet their energy and biosynthetic demands (50, 59). Concurrently, during CHB infection, epigenetic regulatory mechanisms such as DNA methylation and histone modification also undergo changes, subsequently influencing the expression patterns of specific genes (60, 61). Here, our aim is to systematically review the current state of research on immunometabolism and epigenetic modifications in CHB infection, as well as to anticipate their potential applications in future clinical treatments. By delving into these aspects of research, we hope to offer new perspectives and strategies for the treatment and prevention of HBV infection, making a positive contribution to the well-being of individuals affected by HBV infection worldwide.

The regulation of hepatocyte metabolism in CHB is an emerging and significant research area in the development of this disease. Hepatocytes not only act as active drivers of liver inflammation and fibrosis through intercellular communication but also engage in antiviral immunity by secreting type I interferons (IFNs) (66).

IFN serves as a critical initial defense mechanism that exerts control over viral gene replication and expression (67), with its expression directly influencing viral replication. Hepatocytes can trigger innate immune responses through pattern recognition receptors such as Retinoic Acid-Inducible Gene I (RIG-I)-like receptors (RLRs) (68, 69), which recruit the mitochondrial antiviral signaling (MAVS) adaptor (also known as VISA, Cardif, and IPS-1) (70, 71). Upon activation, MAVS molecules aggregate into virus-like supramolecular structures in the mitochondria (72, 73), initiating the activation of transcription factors including IRF3. This activation results in the production of IFN to execute antiviral activities (74, 75).

Recent pivotal studies have elucidated a novel mechanism by which HBV influences immune escape by regulating the immune metabolism of liver cells, thereby affecting their antiviral immune functions (57, 58, 76).

Research on epigenetic modifications in CHB has focused primarily on cccDNA domains. Within the nucleus, the HBV DNA template adopts a minichromosomal structure that interacts with both histone and nonhistone proteins (84). Consequently, epigenetic regulatory mechanisms, including DNA methylation and histone modifications, can influence cccDNA activity, potentially offering new therapeutic concepts for treating chronic hepatitis B (CHB) (85, 86) ( Figure 2.1 ). Conversely, HBV may induce alterations in the host genome at both the genetic and epigenetic levels (86). This dysregulation in gene expression may contribute to the development of CHB infection.

Monocytes/Macrophages, as the primary line of defense against infections, are almost ubiquitously present in various tissues under steady-state physiological conditions. Monocytes/Macrophages exhibit high plasticity and heterogeneity (109). For instance, hepatic macrophages are highly sensitive to the hepatic microenvironment and can rapidly adapt their phenotype (110). HBV infection can polarize macrophages toward an immunosuppressive M2 phenotype, inhibiting the secretion of inflammatory cytokines and stimulating the secretion of the anti-inflammatory cytokine interleukin-10 (IL-10) (111), thereby limiting innate immunity and promoting HBV immune evasion. Consistent with our previous studies, we observed that HBV affects the cytokine secretion functionality of monocytes/macrophages and attenuates their antiviral innate immune responses (112–114).

Metabolism governs the differentiation and function of macrophages (115), whereas epigenetic modifications can directly impact immune function by regulating the activity of metabolic enzymes, thereby influencing energy metabolism (116, 117). Recent studies have demonstrated that HBV-induced hyperacetylation of citrate synthase (CS) and the pyruvate dehydrogenase complex (PDHC) negatively regulates innate immune responses by impairing the TCA cycle in macrophages (105). Mechanistically, HBV activates the TLR2-NF-κB-PGC-1α axis in macrophages, leading to downregulation of the deacetylase SIRT3, thereby increasing acetylation of CS/PDHC and inhibiting their activity, ultimately disrupting the TCA cycle and promoting M2-like polarization of macrophages (105). Additionally, activation of signaling pathways is closely associated with macrophage polarization. AKT signaling activation promotes polarization toward the M2 phenotype, while NF-κB signaling activation suppresses M2 phenotype (118, 119). A recent study on chronic HBV infection suggested that HBV facilitates M2 macrophage polarization through SIRT1-mediated NICD deacetylation, resulting in reduced pro-inflammatory tumor necrosis factor α (TNF-α) and enhanced anti-inflammatory IL-10 expression (120). Mechanistically, HBsAg and HBeAg upregulate the expression of SIRT1 deacetylase, promoting NICD deacetylation, thereby enhancing Akt phosphorylation and inhibiting NF-kB nuclear translocation, ultimately driving M2 macrophage polarization (120).

In summary, HBsAg and HBeAg can, on one hand, upregulate the deacetylase SIRT1, facilitating NICD deacetylation, enhancing Akt phosphorylation, and inhibiting NF-kB nuclear translocation, thereby inducing the formation of immunosuppressive macrophages. On the other hand, HBV can also downregulate the expression of the deacetylase SIRT3 through the TLR2-NF-κB-PGC-1α axis, thereby increasing the acetylation of metabolic enzymes CS/PDHC and inhibiting their activity. This leads to impairment of the TCA cycle and promotion of the M2 phenotype in macrophages ( Figure 3.1 ).

The liver is host to the largest population of tissue-resident macrophages, recognized as Kupffer cells (KCs). During CHB, the HBV employs diverse strategies to manipulate KCs, facilitating infection establishment. This includes inducing KCs to attenuate B cell antibody production (121), inhibiting CD8⁺ T cell cytotoxicity (122), and preferentially producing profibrogenic/anti-inflammatory cytokine TGF-β1 (123) to foster hepatic immune tolerance. A murine study investigating maternally transmitted HBV and its role in vertical virus transmission revealed that HBV can induce an M2-like anti-inflammatory polarization in KCs (124). Subsequent research within this study demonstrated that both M1- and M2-like KCs stimulated by HBV have the capacity to directly inhibit HBV replication in hepatic cells. Mechanistically, the study identified HBV-associated antigens, including HBsAg, HBcAg, and HBeAg, as capable of reprogramming KCs’ metabolism to enhance their OXPHOS activity ( Figure 3.2 ). This reprogramming minimizes host antiviral responses (125). However, the precise mechanisms by which HBV orchestrates metabolic reprogramming in KCs and the impact of immunometabolic alterations on their epigenetic modifications remain elusive. Further investigations in this field hold the potential to unveil novel insights and contribute to a deeper understanding of the intricate interplay between HBV and KCs (125).

As proficient antigen-presenting cells (APCs) integral to the immune system, dendritic cells (DCs) play a pivotal role in bridging the innate and adaptive immune responses (126). The intricate regulation of immunometabolism is recognized as a key determinant influencing the functionality and viability of immune cells, with DCs relying on finely tuned immunometabolic processes to either initiate immune responses or foster immunological tolerance (127). Contrasting the characteristics observed in healthy donors (HD), DCs derived from individuals with CHB manifest impaired antigen presentation capabilities and diminished migratory proficiency (128). A recent investigation within the realm of DCs’ immunometabolism has revealed that HBsAg hampers lipid raft formation and/or low-density lipoprotein receptor (LDLR)-mediated endocytosis on DCs, culminating in diminished levels of free cholesterol during the course of CHB. This impediment in the antigen presentation capacity of DCs precipitates the exhaustion of HBV-specific CD8⁺ T cells, thereby fostering the protracted presence of HBV (129) ( Figure 3.3 ). The findings underscore the intricate interplay between immunometabolism and viral persistence, shedding light on a mechanistic link between HBsAg-mediated alterations in DC function and the sustained evasion of host immune surveillance by HBV.

Cholesterol stands as an essential lipid molecule intricately involved in pivotal biological processes, encompassing lipid rafts and major histocompatibility complex (MHC) molecules (130). Strategies aimed at increasing cholesterol accumulation on DCs can enhance antigen presentation, thus improving the efficacy of therapeutic vaccines and rescuing the exhausted HBV-specific CD8⁺ T cells (129).

Natural killer (NK) cells, as another integral component of the innate immune system (131), play a crucial role in defending against pathogenic infections (132). Our previous research has revealed that HBV utilizes monocytes to modulate NK cells, thereby affecting their regulatory functions and antiviral immunity (112, 113). NK cells secrete TNF-α and IFN-γ, which may contribute to the cytotoxicity involved in HBV clearance (133). In patients with acute HBV infection, NK cells are activated during the acute phase before the adaptive immune response kicks in (134–138). However, during the chronic phase of the disease, NK cells exhibit impaired functionality, which may facilitate viral persistence. Indeed, NK cells from CHB patients show reduced capacity to produce cytokines such as TNF-α and IFN-γ, despite maintaining or even augmenting their cytotoxic capabilities (139–142), a phenomenon referred to as functional dichotomy (139). Additionally, NK cells play crucial roles in shaping and influencing adaptive immune responses by exerting immunomodulatory effects (143).

However, the immune capacity of NK cells at different stages of infection is closely linked to their metabolic phenotypes (144–146). Functional deficiency of peripheral NK cells in patients with CHB is associated with defects in a key metabolic regulatory factor, the mTOR pathway (106). This is primarily manifested by a significant inhibition of cytokine secretion, particularly IFN-γ, while the cytotoxic function remains unaffected in the same environment. The mTOR-mediated metabolic reprogramming has been reported to be closely associated with the function of NK cells (147, 148). Inhibiting mTOR signaling can reduce the rate of glucose uptake and glycolysis in NK cells by inhibiting the key rate-limiting enzymes involved in glycolysis, such as Glut1, Hex2, and Ldha, thereby suppressing lactate production. Furthermore, this pathway is closely related to the expression of IFN-γ in NK cells (149).

Recent studies indicate that epigenetic reprogramming may play a central role in the persistent phenotypic and functional changes in the effector and memory NK cell populations (150). During human cytomegalovirus (HCMV) infection or reactivation, the expanded and host-protective regulated by memory-like NK cell subset demonstrates features of epigenetic reprogramming at genes involved in effector functions and intracellular signaling (151–153). For instance, the enhanced IFN-γ response in these memory-like cells is associated with decreased DNA methylation at the IFNG locus, while the reduced expression of signaling molecules FcϵRIγ and EAT-2 correlates with increased DNA methylation at gene loci (152, 153). Recent ATAC-seq and ChIP-seq studies reveal extensive and highly dynamic epigenetic reprogramming in Ly49H NK cells during the progression of effector, contraction, and memory phases in response to murine cytomegalovirus (MCMV) infection (154). Changes in NK cell chromatin accessibility, particularly at promoter regions, have been shown to directly correlate with transcript abundance changes at early time points after MCMV attack (154), notably for genes related to type I and II interferon signaling, such as Ifng and various ISGs (154). Although there is currently no specific literature on the epigenetic modifications of NK cells under CHB infection, this presents a new avenue for investigating the specific mechanisms underlying NK cell functional defects during CHB infection.

Taken together, HBV regulates the Glut1-Hex2-Ldha-lactate axis-mediated metabolic reprogramming by inhibiting the metabolic regulatory factor mTOR pathway, thereby suppressing the expression of IFN-γ in NK cells ( Figure 3.4 ). Exploring whether HBV regulates epigenetic reprogramming of interferon genes (e.g., methylation, lactylation modifications) by inhibiting the metabolic regulator mTOR pathway and thereby influencing the antiviral function of NK cells would be an intriguing research direction.

T cell exhaustion is a prominent feature of CHB infection (155–158). Energy metabolism in T-cells is closely associated with the function of effector T cells. When T cells experience nutrient deficiency or the inhibition of key metabolic enzymes, their activation and proliferation are suppressed (159–161). Extensive research has highlighted the significant role of glycolytic enzymes in T cell function and activation, such as the crucial glycolytic metabolite phosphoenolpyruvate (PEP) (162) and others (163–165). During HBV infection, despite significantly elevated glucose uptake in severely exhausted virus-specific CD8⁺ T cells, there is impaired oxidative phosphorylation, subsequently affecting their ability to secrete IFN-γ and TNF-α, which correlates with HBsAg levels (107).

In terms of mechanism, HBsAg may inhibit the expression of enolase in exhausted T cells, thereby restricting glycolytic flux. This effect can be enhanced by supplementing downstream product pyruvate (PEP) (107). Additionally,during HBV infection, functional and non-exhausted T cells can utilize oxidative phosphorylation (OXPHOS) to meet their energy demands. In contrast, exhausted T cells exhibit dysfunctional depolarized mitochondria despite increased expression of glucose transporter-1 (GLUT-1), indicating impaired OXPHOS function, which subsequently affects the antiviral immune function of T cells (166). Consequently, the compromised functionality of HBV-specific CD8⁺ T cells does not stem from a deficiency in glucose uptake but rather from their diminished ability to engage OXPHOS to meet their energy demands. This deficiency hampers the capacity of T cells for metabolic reprogramming, transitioning from glycolysis to OXPHOS, which is essential for fulfilling the bioenergetic requisites crucial for the establishment of protective T cell memory (167). Recent investigations have further validated this underlying mechanism, with studies indicating that addressing mitochondrial dysfunction can effectively restore the antiviral activity of exhausted HBV-specific CD8⁺ T cells in CHB (168).

A recent authoritative review on the metabolic and epigenetic regulation of T cell exhaustion proposed that changes in mitochondrial adaptability and dynamics may drive epigenetic alterations that enhance T cell exhaustion, further impeding T cell immune function by influencing chromatin accessibility (169). This review highlights acetyl-CoA as a plausible candidate with potential supporting evidence. Under aerobic conditions, pyruvate generated from glycolysis enters the tricarboxylic acid (TCA) cycle in the mitochondria to produce acetyl-CoA [31], and the levels of acetyl-CoA are highly dependent on glucose availability and mitochondrial respiratory function (170). Acetyl-CoA forms the basis for the functions of histone acetyltransferases (HATs) (53). Evidence has long established that the availability of acetyl-CoA regulates many protein acetylation modifications (52, 171, 172). A mouse study demonstrated that reducing the levels of acetyl-CoA led to decreased acetylation of lysine 9 residues on histone H3 at the IFNG gene locus in CD4⁺ T cells, thereby suppressing IFNG expression (59). Additionally, promoting histone acetylation and chromatin accessibility can restore IFN-γ secretion in CD8⁺ T cells under glucose-restricted conditions (173).

Together, HBsAg can inhibit the key metabolic enzyme enolase, leading to the depolarization of exhausted T-cell mitochondria, manifested as impaired OXPHOS function ( Figure 3.6 ). This specific alteration in metabolic reprogramming may lower acetyl-CoA levels, subsequently inhibiting the acetylation levels of target genes (IFN-γ and TNF-α), hindered the antiviral immune function of T cells.

Functioning as essential components of the humoral immune system, B cells play a pivotal role in generating antibodies against HBV (174). Notably, recent studies have focused on investigating deficiencies in both intrahepatic and circulating antiviral B cell responses in individuals with hepatitis B (175–177). Persistent viral infections can compromise the various antiviral functions of B cells, including antigen presentation, humoral immunity, and cytokine production (178–180). The activation status of B cells is closely related to their metabolic pathways. Unlike T cells, activated B cells lead to a wide-ranging increase in metabolism, including enhanced oxygen consumption and extracellular acidification rates (181).

During CHB infection, the virus inhibits the metabolic capacities of B cells, including OXPHOS and glycolysis. This, in turn, affects the energy supply and effector secretion of B cells, leading to a decrease in their proliferation and differentiation abilities, thereby facilitating the sustained presence of HBV (108). Mechanistically, HBV suppresses the AKT/mTOR pathway in B cells, reducing their glucose uptake and causing mitochondrial dysfunction, specifically by impairing OXPHOS function (108). Because OXPHOS provides 85% of the total ATP in activated PBMCs (182), HBV virus impairs the production of ATP in B cells by compromising both glycolysis and OXPHOS functions, thereby attenuating the activation of B cells.

Additionally, epidemiological studies have shown an increased risk of Non-Hodgkin’s lymphoma (NHL) in individuals with CHB infection, indicating a significant correlation (183, 184). Furthermore, recent clinical cohort studies on HBV and B cells have identified a higher occurrence of mutations in the key epigenetic regulator, ARID1A, in HBV cases (185, 186). Notably, HBV-related HCC also exhibits a high frequency of ARID1A mutations (187). ARID1A encodes a subunit of the Switch/Sucrose-Nonfermentable (SWI/SNF) chromatin remodeling complex, which primarily regulates chromatin accessibility to allow for the activation of target gene transcription. Importantly, its function in chromatin remodeling is ATP-dependent (188). Subunits of the SWI/SNF complex are crucial for the expression of B lineage-specific genes and the development of B cells (189).

Collectively, HBV impairs the glycolytic and OXPHOS metabolic functions of B cells by inhibiting the AKT/mTOR pathway ( Figure 3.5 ). This inhibition leads to a reduction in ATP production, and the expression of the ATP-dependent epigenetic modification complex (SWI/SNF) responsible for promoting chromatin accessibility, ultimately affecting the antiviral immune response of B cells.

In HBV-infected hepatocytes, the virus can modulate the epigenetic modifications of downstream target genes (such as IFN) by regulating immunometabolism, thereby exerting an impact on antiviral immunity. HBV influences the antiviral immune response and viral replication in hepatocytes by intervening in the glycolytic and PPP metabolic pathway ( Figure 1 ). Specifically, the primary outcomes of the impact of HBV on hepatocyte glycolysis are an increase in the metabolic product lactate and suppression of IFN production (58). Coincidentally, lactate derived from glycolysis acts as a threshold inhibitor of IFN production when RLR is activated, providing strong evidence of a negative regulatory relationship between lactate and IFN (190). This underscores the importance of lactate as a crucial metabolic product in innate immune responses in hepatocytes during CHB infection. Notably, a new epigenetic modification, lactylation, was discovered four years ago, elevating our understanding of lactate to unprecedented levels (51). Lactate-driven lactylation modifications play a vital role in suppressing inflammation and immune processes, making them a popular topic in recent research (191, 192). Therefore, exploring whether lactate, through its induced lactylation modifications, reduces the accessibility of IFN gene chromatin, thereby inhibiting the antiviral immune response in hepatocytes, would be an intriguing research direction. Lactate-induced lactylation may serve as a bridge between immunometabolism and antiviral effects.

Concomitantly, HBV promotes the hepatocellular PPP metabolism and sustains viral replication (57, 76). One of the main functions of the PPP is the generation of NADPH (193), which is an indispensable reducing agent in synthetic metabolic processes. The upregulation of HBx in hepatocytes increases the production of intracellular ATP and NADPH (194). Recent research revealed that NADPH can interact with histone deacetylase 3 (HDAC3), inhibiting its activity by disrupting its binding with co-factors (195). Simultaneously, in studies on hepatocytes, overexpression of the deacetylase HDAC3 can inhibit HBV replication (196). Recent studies have found a direct correlation between deacetylase and the production of type I interferons in innate immunity. In U3OS cells infected with Sendai virus (SeV), acetyl groups are present at specific DNA-binding domain (DBD) sites of IRF3/IRF7, thereby eliminating the liquid-liquid phase separation (LLPS) and IFN-I induction of IRF3/IRF7 (197). In other words, inhibiting deacetylases can block IFN signal transduction, thereby promoting viral replication. This further supports the conclusion that HBV protein expression interferes with the transmission of type I IFN signaling in infected hepatocytes (198). In summary, HBV increases the accumulation of NADPH, a product of PPP metabolism, in hepatocytes. NADPH may potentially interact with HDAC3, inhibiting deacetylase activity, which promotes the acetylation of the DNA-binding domain (DBD) of IRF3/IRF7. This, in turn, suppresses IFN expression and facilitates viral replication.

From a metabolism-epigenomics perspective, metabolites can serve as substrates or cofactors for epigenetic modifications, thereby altering the structure and function of chromatin and genomic regions associated with diseases (55). Epigenetic modifications can also directly impact energy metabolism and thus influence immune function by either regulating the transcription levels of metabolic enzymes or affecting the activity of metabolic transcription factors (117, 199). This intricate interplay creates a complex network between immunometabolism and epigenetics in CHB infection. In our recent study, we found that HBV can induce immunometabolism and epigenetic reprogramming in monocytes/macrophages, subsequently influencing their functionality and fate (to be published). Therefore, in-depth research into immunometabolism and epigenetic reprogramming will provide new perspectives for understanding the mechanistic origins of CHB.

Furthermore, as described above, exploring the relationships between immunometabolism and epigenetic modifications in various immune cells will be a captivating and highly meaningful research direction. Firstly, it remains an intriguing question whether HBV modulates the epigenetic reprogramming of interferon genes, such as methylation and lactylation, by inhibiting the metabolic regulatory factor mTOR pathway, consequently impacting the antiviral function of NK cells. Secondly, despite HBV inducing specific T cell exhaustion, leading to mitochondrial dysfunction and affecting the secretion of IFN-γ and TNF-α (107), the intricate mechanisms underlying the metabolic reprogramming and altered antiviral activity in T cells remain elusive. The potential reduction of acetyl-CoA levels in T cells through HBV-induced OXPHOS metabolic reprogramming may inhibit the acetylation levels of target genes, such as IFN-γ and TNF-α, representing a profound mechanism underlying the immune deficiency in exhausted T cells. Lastly, HBV, by suppressing the glycolysis of B cells, not only impairs the activation of B cells but also inhibits ATP levels within B cells and the expression of the ATP-dependent epigenetic modification complex SWI/SNF, both of which may synergistically further compromise the antiviral immune response of B cells.

HBV affects metabolic reprogramming of hepatocytes through various pathways, leading to increased lactate production (57, 58). Lactate is a metabolic intermediary that shapes the fate and function of immune cells (200). Lactate plays a key role in oxidation, gluconeogenesis, and cellular signal transduction (201–203). Endogenous lactate is primarily produced through aerobic or anaerobic glycolysis, whereas exogenous lactate primarily enters the cells via monocarboxylate transporters (MCTs) (204) and G protein-coupled receptor 81 (GPR81) (GPR81) (205). MCT-1 mediates the effects of lactate on macrophages and CD8⁺ T cells (50, 206), potentially providing lactate as a messenger from hepatocytes to regulate immune cells. A decade ago, research indicated that exogenous lactate could induce the polarization of macrophages toward the M2 phenotype, manifested by increased expression of VEGF and ARG1 (50). Similarly, recent findings suggested that lactylation modifications specifically induced by lactate promote the expression of VEGF and ARG1 in macrophages (51). Furthermore, in the field of lactate research, predominantly focused on tumors, physiologically relevant concentrations of lactate can inhibit the activation of CD8⁺ T and NK cells, resulting in reduced production of IFN-γ (207). Tregs can absorb and metabolize lactate, thereby sustaining their suppressive function in environments characterized by elevated lactate levels, as observed in contexts such as the tumor microenvironment (208). Whether lactate-mediated inhibition of IFN-γ secretion in NK and T cells is facilitated through lactylation modifications presents an intriguing avenue for exploration.