HBV and host metabolic crosstalk: Reprogramming pathways for viral replication and pathogenesis

Abstract

Hepatitis B virus (HBV) establishes chronic infection through strategic manipulation of host metabolic networks, driving a spectrum of hepatic pathologies ranging from hepatitis to cirrhosis and hepatocellular carcinoma. Mechanistically, HBV reprograms core metabolic pathways, including glycolysis, tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and lipid homeostasis, to fuel its replication machinery and evade immune surveillance. This review systematically synthesizes current evidence on HBV-induced glucose/lipid metabolic rewiring, with particular emphasis on how viral-host crosstalk at the metabolic interface sustains viral pathogenesis.

Highlights

• •HBV exploits host glucose/lipid metabolism to boost viral replication.
• •Viral proteins HBx/HBsAg hijack key metabolic pathways.
• •Metabolic interventions show promise for anti-HBV therapy.

Introduction

The liver serves as the body's primary metabolic hub, orchestrating systemic homeostasis through precise regulation of carbohydrate, lipid, and amino acid metabolism. This metabolic dominance, governed by intricate transcriptional networks in hepatocytes (80% of liver mass), stems from their unique endoplasmic reticulum (ER) and mitochondrial abundance (Rui, 2014; Gissen and Arias, 2015). While essential for physiological balance, these features render the liver vulnerable to pathological exploitation–particularly during chronic viral hepatitis infections where metabolic reprogramming drives disease progression.

HBV, a small enveloped DNA virus from the Hepadnaviridae family, primarily infects hepatocytes and establishes chronic infection in millions worldwide, representing a leading cause of cirrhosis and hepatocellular carcinoma (HCC) (Hsu et al., 2023). It exists as three particle types in infected sera: infectious 42-nm Dane particles containing rcDNA polymerase complexes, and non-infectious 22-nm spherical and filamentous particles. The viral envelope incorporates three co-terminal glycoproteins-small (S), medium (M), and large (L) surface antigens-that mediate viral entry and assembly. HBV predominantly utilizes the ER-Golgi-endosomal pathway for particle secretion, while persistent infection-induced ER stress promotes autophagosome-mediated alternative trafficking of viral components (Wang, X. et al., 2022a; Wang, X. et al., 2022b). While antiviral therapies can suppress HBV replication, they cannot eliminate the virus due to the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected cells (Hu and Huang, 2024).

HBV strategically hijacks hepatic metabolism to fuel replication and evade immunity (Bard-Chapeau et al., 2014; Xie et al., 2017; Diaz et al., 2022; Willmann and Moita, 2024). Clinical metabolomic studies reveal progressive dysregulation of tricarboxylic acid (TCA) cycle and lipid pathways during disease progression (Yang et al., 2016; Li J. et al., 2022), whereas HBV surface antigen (HBsAg) seroclearance correlates with suppressed glycolysis/gluconeogenesis gene activity, enhanced fatty acid (FA) degradation, and elevated TCA metabolites (Lin et al., 2025). Mechanistically, HBV disrupts hepatic glucose homeostasis via direct interactions between viral proteins and host enzymes. The HBV X protein (HBx) and HBsAg modulate key rate-limiting enzymes in glycolysis and gluconeogenesis, such as PKM2 and phosphoenolpyruvate carboxykinase (PEPCK), at both transcriptional and post-translational levels (Wang and Zhang, 2023), forcing hepatocytes to turn to the “Warburg effect” to enrich ATP and raw materials required for viral replication. This regulation is further reinforced by liver-enriched transcription factors that directly modulate HBV activity through specific binding sites present in viral promoters (Turton et al., 2020). Moreover, truncated HBx proteins generated through viral genome integration further perturb redox balance, creating a microenvironment conducive to viral persistence (Zhang, Y. et al., 2021). Lipid metabolism is similarly hijacked in a stage-specific manner: early infection promotes lipid droplet formation for capsid assembly, while cirrhosis stage suppresses cholesterol synthesis (Arain et al., 2018; Zhang, J. et al., 2021). Notably, HBx alone suffices to alter hepatocyte lipid profiles (Lamontagne et al., 2018). Moreover, nutrient availability dynamically regulates HBV production via autophagy-mediated processes, revealing a sophisticated crosstalk between host metabolic pathways and viral propagation.

Notably, these metabolic remodeling events exhibit spatiotemporal heterogeneity and are precisely coupled to the different stages of the viral life cycle. However, a comprehensive, systematic analysis of the dynamic regulatory networks governing HBV-induced metabolic reprogramming and its interaction with the host immune microenvironment remains lacking. This review aims to integrate clinical data with molecular mechanism studies, summarize the multi-level regulatory framework of HBV metabolic interactions, and discuss the potential of key metabolic molecules as innovative therapeutic targets.

Metabolic architecture hijacked by HBV

Glucose metabolic rewiring

Glycolytic flux amplification (Warburg-like reprogramming)

HBV strategically rewires host glucose metabolism to support viral replication and persistence, primarily through hijacking glycolysis (including the TCA cycle), the pentose phosphate pathway (PPP), and the hexosamine biosynthesis pathway (HBP) (Fig. 1i–iii). Under normal physiological conditions, most glucose undergoes oxidative phosphorylation (OXPHOS) under aerobic conditions (Cooper and Adams, 2009), but HBV infection induces a Warburg-like shift—viruses induce host cells prioritizing aerobic glycolysis despite oxygen availability (Koppenol et al., 2011; Dayton et al., 2016).

Fig. 1.

Interactions between HBV and glucose metabolism. i–iii. HBV upregulates glycolysis and glucose bypass pathways to maintain its own requirements by activating key enzymes, including hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), Glucose-6-phosphate dehydrogenase (G6PD), transketolase (TKT), and fructose-6-phosphate amidotransferase (GFAT). iv. Upregulation of monocarboxylate transporter protein 1 (MCT1) promotes proliferation of HBx-expressing cells via lactate. v. HBV integrates its genome into mitochondrial DNA (mtDNA), affecting mitochondrial function. vi. HBV impairs the TCA cycle by inhibiting pyruvate dehydrogenase complex (PDH) and citrate synthase activity in anti-inflammatory M2-like macrophages and causing mitochondrial dysfunction in CD8⁺ T cells and B cells. vii. Glycogen synthase (GYS) is down-regulated after HBV infection, with decreased glycogen synthesis and increased utilization. viii. HBx and small hepatitis B virus surface antigens (SHBs) activate phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase)-associated gluconeogenesis. Fructose-1,6-bisphosphatase 1 (FBP1) was also upregulated. Abbreviations: G-6-P: glucose 6-phosphate. F-6-P: fructose 6-phosphate. R-5-P: Ribose-5-phosphate. GlcN-6-P: Glucosamine-6-phosphate. Pyr: pyruvate. OAA: oxaloacetic acid. CA: citrate.

The specific features of this reprogramming include: 1). Upregulation of oxygen-independent glycolytic flux: HBV enhances the expression or activity of key glycolytic enzymes, leading to increased glucose uptake and lactate production. The viral protein HBx directly binds to the promoter of NF-κB p65 and promotes nuclear translocation to enhance the transcription of hexokinase 2 (HK2)—the rate-limiting enzyme catalyzing the first step of glycolysis, thereby increasing glucose-6-phosphate production (Chen, L. et al., 2022), fueling both glycolysis and biosynthetic pathways. In parallel, the HBS region of the HBV envelope proteins interact with the C-terminus (aa 367–476) of pyruvate kinase M2 (PKM2), promoting its dimerization and reducing its enzymatic activity at the final step of glycolysis (Wu, Y.H. et al., 2021). This interaction creates a metabolic bottleneck that rediverts glycolytic intermediates toward PPP and nucleotide synthesis—processes critical for HBV replication and implicated in oncogenic transformation in preclinical models (Dayton et al., 2016). 2). Mitochondrial function inhibition: Viral infection reduces mitochondrial oxidative phosphorylation efficiency, disrupts mitochondrial membrane potential, and promotes ROS accumulation, causing host cells to rely on glycolysis for energy supply (Foo et al., 2022). A key study revealed that HBV polymerase contains a mitochondrial-targeting sequence that redirects mitochondrial function to favor viral replication, simultaneously generating biosynthetic intermediates and fostering an immunosuppressive microenvironment (Unchwaniwala et al., 2016).

Lactate accumulation primarily impairs the function of hepatic immune cells, thereby establishing an immunosuppressive microenvironment that facilitates viral persistence. Elevated lactate levels not only impair the innate immune response by regulating mononuclear-macrophages, neutrophils, dendritic cells and natural killer (NK) cells, but also lead to CD8⁺ T cell dysfunction (Colegio et al., 2014; Deng et al., 2021; Liu, H. et al., 2024; Plebanek et al., 2024; Jin et al., 2025). It is worth noting that lactate exported via monocarboxylic acid transporter 1 (MCT1) activates the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT/PKB) signaling pathway (Fig. 1 iv) (Chen, L. et al., 2022), driving the malignant proliferation of HBV-infected hepatocytes. Additionally, lactate-driven histone lactation epigenetically reprograms the gene expression of metabolic enzymes to maintain a favorable environment for viral persistence (Zhang, D. et al., 2019; Gao et al., 2023; Jin et al., 2023; Yang, Z. et al., 2023).

HBV further fine-tunes this metabolic landscape through miRNA-mediated regulation. HBV exploits pro-viral miRNAs (e.g. miR-30b-5p) to enhance glycolytic flux supporting infected hepatocyte proliferation (Chen, W. et al., 2021). While host countermeasures employ antiviral miRNAs (e.g. miR-130a) that target key metabolic regulators, such as peroxisome proliferator-activated receptor γ-coactivator 1-α (PGC1α), peroxisome proliferator-activated receptor γ (PPARγ), and the gene encoding pyruvate kinase in liver and red blood cells (PKLR) (Huang, J.Y. et al., 2015; Duan et al., 2018), to restore metabolic balance and limit viral replication. This intricate interplay underscores HBV's ability to exploit host metabolism while evading immune surveillance.

Hexosamine biosynthetic axis and pentose phosphate pathway: glucose metabolism bypass activation

HBV infection strategically activates host glucose metabolism bypasses to support viral replication and carcinogenic processes. This metabolic reprogramming primarily involves two key pathways: the HBP, which contributes to protein glycosylation and modulates cellular signaling to regulate HBV replication; and the PPP, a critical glucose metabolism bypass that provides ribose sugars for nucleotide synthesis and generates nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) to support reductive biosynthesis and counteract oxidative stress.

• 1).The HBP. A pivotal study demonstrated that HBV upregulates glucose transporter 1 (GLUT1) and glutamine-fructose-6-phosphate amidotransferase (GFAT) (Li, H. et al., 2015), two key enzymes of HBP, increasing production of UDP-GlcNAc—the substrate for O-GlcNAcylation. This post-translational modification exerts dual effects: O-GlcNAcylation of RNA N⁶-methyladenosine (m6A) reader YTH domain 2 (YTHDF2) promotes HBV replication (Yang, Y. et al., 2023), whereas O-GlcNAcylation of sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1, a viral restriction factor) inhibits its phosphorylation, paradoxically suppressing HBV activity (Hu et al., 2021). Notably, pharmacological inhibition of HBP presents a paradoxical effect on HBV infection and hepatocarcinogenesis. Our previous study revealed that blocking HBP with small-molecule inhibitors (OSMI-1) unexpectedly enhanced HBV replication and gene expression despite reducing UDP-GlcNAc levels (Wang, X. et al., 2020). Mechanistically, HBP inhibition triggered ER stress, activating the unfolded protein response (UPR) pathway, which in turn upregulated viral transcription. Furthermore, HBP suppression impaired autophagic flux by blocking autophagosome-lysosome fusion, leading to accumulation of defective autophagosomes that may provide membrane scaffolds for HBV assembly and fusion with membrane for viral egress. Intriguingly, while HBP inhibition promoted viral persistence, it simultaneously suppressed hepatocellular carcinoma progression by reducing O-GlcNAcylation of oncogenic signaling molecules (e.g., eEF1A1, YTHDF2) (Yang, Y. et al., 2023; Zhou et al., 2023). This dichotomy suggests a context-dependent role of O-GlcNAcylation in balancing viral fitness and oncogenesis.
• 2).The PPP, another critical glucose metabolism bypass, meets HBV's biosynthetic demands by generating NADPH and ribose-5-phosphate via glucose-6-phosphate dehydrogenase (G6PD) and transketolase (TKT) (Liu, Qi et al., 2022). In HBV-associated HCC, both G6PD and TKT are elevated, reflecting heightened nucleotide synthesis (Kittaka et al., 2010). Mechanistically, HBx activates the NF-E2-related factor 2 (Nrf2), to promote G6PD expression, anti-apoptotic factors (Bcl-2, Bcl-xl) and cell cycle proteins (Liu, B. et al., 2015). Additionally, HBx stimulates signal transducer and activator of transcription 3 (STAT3) phosphorylation at Tyr-705 and promoted the activity and downstream signaling pathway of STAT3 via the SH2D5-TKT interaction, accelerates nucleotide synthesis, and promotes HCC proliferation (Zheng, Y. et al., 2019).

Together, HBV has engineered a complex metabolic reprogramming network that exploits HBP and PPP to optimize viral replication while creating a pro-tumor microenvironment. The dual roles of O-GlcNAcylation and the G6PD-Nrf2-STAT3 axis highlight the delicate balance between viral persistence and host metabolic fitness, providing new therapeutic targets for disrupting HBV-associated carcinogenesis.

Mitochondrial reprogramming strategy

Under normal physiological conditions, the TCA cycle serves as the central hub of mitochondrial metabolism, fueling ATP production and generating reducing equivalents to sustain cellular energy demands (Arnold and Finley, 2023). However, HBV subverts these canonical metabolic pathways to meet its heightened requirements for replication and secretion, driving extensive reprogramming of mitochondrial glucose metabolism (Fig. 1 vi) (Vander Heiden et al., 2009; Li, Y. and Ou, 2023). In HCC, cellular methylation sequencing reveals that HBV-induced epigenetic modifications predominantly disrupt three interconnected metabolic processes: glycolysis, the TCA cycle, and OXPH-OS (Ye et al., 2016). Notably, HBV preferentially integrates its genetic material into mitochondrial DNA (mtDNA) at loci critical for energy production, such as cytochrome C oxidase III, a key OXPHOS component (Fig. 1 v) (Oikawa et al., 2022). This integration disrupts OXPHOS efficiency while paradoxically enhancing glycolytic flux, thereby redirecting glucose-derived carbons to support viral replication (Giosa et al., 2023). Such metabolic rewiring not only sustains HBV propagation but also impairs immune surveillance by modulating the metabolic states of host immune cells.

The metabolic interplay between HBV and immune cells exhibits polarization-dependent dynamics. In pro-inflammatory M1-like macrophages, HBV upregulates OXPHOS to suppress IL-1β expression, effectively neutralizing its antiviral activity and facilitating viral persistence (Li, Y. et al., 2022). Conversely, in anti-inflammatory M2-like macrophages, HBV induces hyperacetylation of mitochondrial enzymes, including citrate synthase and the pyruvate dehydrogenase complex (PDH), to inhibit pyruvate-derived acetyl coenzyme A production, subsequently limiting pyruvate flux into the TCA cycle (Bei et al., 2023; Selvamani et al., 2024). This metabolic constraint may trigger compensatory glutamine anaplerosis to replenish the TCA intermediates, which has been shown to further facilitate HBV transcription and replication (Raney et al., 1991; Murad et al., 2021; Cheng, S.T. et al., 2025). HBV further extends its metabolic manipulation to adaptive immunity (Wang, L. et al., 2023). In activated CD8⁺ T cells, HBV infection leads to mitochondrial dysfunction, shifting metabolism from OXPHOS to aerobic glycolysis, which compromises effector functions and antiviral response (Schurich et al., 2016). Similarly, B cell in HBV-associated cirrhosis exhibits impaired mitochondrial function, leading to defective proliferation and differentiation—a metabolic defect that exacerbates infection-related complications (Huang, C. et al., 2021).

HBV orchestrates a multifaceted metabolic hijacking strategy, targeting mitochondrial metabolism to fuel its replication while simultaneously crippling host immune defenses. This dual mechanism underscores the potential of metabolic pathway modulation as a therapeutic avenue to disrupt viral persistence and restore immune competence in chronic HBV infection.

Glycogen metabolic dysregulation

Glycogen synthesis and utilization

Glycogen, primarily stored in the liver and muscles, serves as a crucial reservoir for maintaining blood glucose homeostasis. Intrahepatic glycogen plays a vital role in sustaining glucose levels, particularly during fasting states. However, in the context of HBV infection and its progression to HCC, a metabolic shift occurs, characterized by the transition from glycogen storage to glycogen utilization (Toshkov et al., 1994). This shift is accompanied by an enhancement of glycolysis. Glycogen synthase (GYS), a key enzyme responsible for glycogen synthesis, is downregulated in HBV-related HCC (Chen, S.L. et al., 2019). Additionally, mutations in the pre-S2 region of HBV may trigger glycolysis, thereby promoting glycogen utilization (Fig. 1 vii) (Teng et al., 2015). HBx may exhibit inhibitory effects on glycogen synthesis, thereby disrupting hepatocyte terminal differentiation and fostering cellular proliferation (Huang, J. et al., 2012). Additionally, HBx contributes to hepatocarcinogenesis by activating the AKT/glycogen synthase kinase (GSK-3β)/β-catenin signaling pathway (Khattar et al., 2012), further promoting tumorigenesis. Glycogen synthase kinase 3 (GSK3) inhibitors can suppress the production of HBV e antigen (HBeAg) and HBsAg (Nishitsuji et al., 2025).

Gluconeogenesis pathway

In fasting conditions, glucagon binding to the glucagon receptor (GCGR) upregulates key gluconeogenic enzymes, including PEPCK and glucose-6-phosphatase (G6Pase). Notably, the small hepatitis B virus surface antigen (SHBs) has been shown to activate these gluconeogenic steps by directly binding to the adenylyl cyclase (AC) 1 promoter (Chen, Y. et al., 2022). The CREB-regulated transcription coactivator 2 (CRTC2) plays a significant role in this process. When activated, CRTC2 enhances HBV transcription and replication through induction of PGC1α, a central regulator of gluconeogenesis, thereby establishing a direct link between hepatic metabolic signaling and viral biosynthesis (Tian et al., 2014). Conversely, phosphoenolpyruvate carboxykinase 1 (PCK1), the mitochondrial isoform of PEPCK, inhibits HBV replication by suppressing the activity of PGC1α (Fig. 1 viii) (Tang et al., 2019). HBx further regulates hepatic metabolic pathways by interacting with critical transcription factors, including PGC1α, and regulating the expression of nuclear receptors (NRs), such as hepatocyte nuclear factor 4-α (HNF4α) and forkhead box protein O1 (FOXO1) (Fig. 2 viii) (Haviv et al., 1995; Reese et al., 2011; Tian et al., 2013). These transcription factors are not only involved in HBV promoter regulation but also contribute significantly to viral transcription. Short-term fasting enhances hepatic gluconeogenesis via activation of PGC1α, which in turn induces HBV expression (Shlomai et al., 2006; Shlomai and Shaul, 2009). Although caloric restriction does not significantly impact the HBV life cycle in hydrodynamic injection models, prolonged observation suggests that its effects may become more pronounced over time (Li, L. et al., 2009). Consequently, targeting PGC1α has been proposed as a potential therapeutic strategy for HBV treatment (Jhuang et al., 2015), offering a promising approach to modulate both viral replication and host metabolic pathways.

Fig. 2.

Interactions between HBV and lipid metabolism. i. HBx enhances fatty acid oxidation (FAO). ii. HBV promotes lipid synthesis and lipid droplet accumulation. iii. HBx enhances the synthesis of unsaturated fatty acid derivatives, including prostaglandins and leukotrienes. iv. HBV upregulates cholesterol 7α-hydroxylase activity, which converts cholesterol to bile acids. v. Acyl coenzyme A-cholesterol acyltransferase (ACAT) is involved in the esterification of free cholesterol. Inhibition of ACAT reduce the production of HBV virus particles. vi. Serum phosphatidylcholine (lecithin), phosphatidylethanolamine (ceruloplasmin), and lysophosphatidic acid were increased, whereas phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, and sphingomyelin were decreased in HBsAg-positive patients. vii. The HBV envelope is enriched with apolipoprotein E (ApoE), which promotes HBV infection and production upon binding to the low-density lipoprotein receptor (LDLR). HBV enters hepatocytes via the sodium taurocholate cotransporting polypeptide (NTCP), a transporter receptor for bile acids. viii. HBx interacts with PGC1α to regulate nuclear receptor (NR) expression, modulate hepatic metabolism, and promote its own transcription.

In addition to these mechanisms, HBx activates the transcription initiation site of iNOS promoter, initiating the nitric oxide (NO)/c-Jun N-terminal kinase (JNK) signaling pathway to activate gluconeogenesis, thereby promoting the expression of key enzymes of gluconeogenesis, including PEPCK, and G6Pase (Shin et al., 2011). Furthermore, fructose-1,6-bisphosphatase 1 (FBP1), another critical gluconeogenic enzyme, is subject to epigenetic modulation in the context of HBV infection (Fig. 1 viii) (Sengupta et al., 2022). Collectively, these findings underscore the intricate interplay between HBV infection and hepatic gluconeogenesis metabolism, highlighting novel metabolic targets for therapeutic intervention.

Lipid metabolic reprogramming

Fatty acid metabolism manipulation in HBV infection

HBV extensively rewires host FA metabolism to establish a favorable environment for viral replication and persistence. The virus primarily modulates FA metabolism through its regulatory protein HBx, which orchestrates a metabolic shift toward both fatty acid oxidation (FAO) and lipogenesis. HBx promotes calcium mobilization into the cytoplasm, thus stimulates AMP-activated protein kinase (AMPK) to enhance FAO (Fig. 2 i), enabling energy production under nutrient stress (Wang, M.D. et al., 2016), while simultaneously upregulating lipogenic factors sterol regulatory element-binding protein 1 (SREBP1) and PPARγ to drive lipid accumulation and unsaturated FA derivative synthesis (Fig. 2 ii, iii) (Kim, K.H. et al., 2007; Shan et al., 2010). The virus exhibits a complex, species-dependent relationship with FAs: long-chain FAs (e.g., palmitic acid) stabilize HBx and promote replication (Okamura et al., 2016; Wu, Y.L. et al., 2016; Huang, J. et al., 2017; Zhang, W. et al., 2025), whereas short-chain FAs demonstrate protective effects against HCC progression (Mcbrearty et al., 2021), and exogenous oleic acid paradoxically suppresses HBV secretion (Liu, Qichuang et al., 2022). HBV further optimizes its FA environment by upregulating FABP1 to retain pro-viral long-chain FAs (Wu, Y.L. et al., 2016) while reducing anti-viral short-chain FA levels (Zhang, W. et al., 2025). Additionally, clinical observations reveal enhanced FAO as a key metabolic feature in HBV-related ACLF and suggest that inhibiting FAO with trimetazidine improves patient survival (Yu et al., 2020).

Chronic HBV infection is epidemiologically linked to a lower prevalence of hepatic steatosis and more favorable lipid profiles, raising questions about the underlying mechanisms. Rather than reflecting a benign viral effect, this “protective” phenotype arises from virus-host interplay involving metabolic reprogramming and immunomodulation. Cheng et al. (2023) showed that HBV-monoinfected individuals have reduced serum triglycerides, cholesterol, LDL, and HDL, suggesting HBV suppresses lipogenesis (Cheng, Y.M. et al., 2023). Mechanistically, HBx may disrupt nuclear receptor signaling (e.g., PPARα, LXR), diverting lipid precursors toward viral replication. In parallel, HBV modulates immunity: Huang et al. (2024) reported that chronic hepatitis B (CHB) patients with metabolic dysfunction-associated steatotic liver disease (MASLD) achieved higher rates of HBsAg clearance (Huang, S.C. et al., 2024). HBx inhibits inflammasome activation (e.g., NLRP3), and HBV-driven lactate accumulation impairs NK, dendritic, and CD8⁺ T cell function, fostering immunosuppression. Nevertheless, this apparent protection is paradoxical and context-dependent. CHB patients, especially those with high HBV DNA levels, show reduced steatosis (Huang, S.C. and Liu, 2023; Liu, C.J. et al., 2024), but once MASLD develops, metabolic and viral insults synergize to accelerate fibrosis. Thus, HBV may initially suppress steatosis via metabolic and immune pathways, but metabolic dysfunction ultimately unmasks and amplifies its pathogenic potential. This intricate interplay between HBV and FA metabolism not only supports viral replication but also contributes to HBV-related liver disease progression, offering novel avenues for therapeutic intervention.

Cholesterol metabolic reprogramming by HBV

HBV critically depends on cholesterol for multiple lifecycle stages, particularly viral entry and assembly, as demonstrated by significantly reduced infectivity following membrane cholesterol depletion (Bremer et al., 2009; Pollock et al., 2010). Recent study demonstrated that inhibition of acyl-CoA:cholesterol acyltransferase (ACAT), a key enzyme in cholesterol esterification, exerts triple therapeutic benefits: directly suppressing HBV particle genesis, restoring exhausted T cell function through lipid metabolism reprogramming (reducing neutral lipid droplets while enhancing TCR signaling), and synergizing with programmed death receptor 1 (PD-1) blockade to rejuvenate antiviral immunity (Schmidt et al., 2021) (Fig. 2 v). HBV may manipulate cholesterol metabolism through oxidized cholesterol derivatives that activate Liver X receptor (LXR) nuclear receptors to promote viral transcription (Kim et al., 2011; Cui, M. et al., 2014). Paradoxically, although HBV exploits cholesterol for replication, restoration of cholesterol homeostasis can enhance antiviral immunity by improving dendritic cell function (Zhao et al., 2022), highlighting the complex interplay between viral requirements and host defenses. Furthermore, HBV profoundly alters bile acid metabolism through upregulation of cholesterol 7α-hydroxylase (Fig. 2 iv) and modulation of the sodium taurocholate cotransporting polypeptide (NTCP) receptor (Fig. 2 vii) (Geier, 2014; Oehler et al., 2014), creating additional metabolic vulnerabilities that could be therapeutically targeted.

Phospholipid exploitation in HBV assembly and entry

Mounting evidence demonstrated that HBV extensively rewires host phospholipid metabolism to facilitate its lifecycle (Shi et al., 2024; Zhang, L. et al., 2024), with the HBsAg playing a pivotal role in this process. Seminal work by Satoh et al. first biochemically characterized HBsAg as phosphatidylcholine-enriched particles (Satoh et al., 1990), establishing the fundamental lipid composition of HBV envelopes. Building on this foundation, Núñez and colleagues revealed the structural mechanism by which the preS domain mediates membrane fusion by inserting into host phospholipid bilayers (Núñez et al., 2009). These molecular insights correlate with clinical observations showing characteristic alterations in serum phospholipid profiles of HBsAg-positive patients, including elevated phosphatidylcholine (PC), phosphatidylethanolamine (PE), and lysophosphatidic acid (LPA), alongside decreased phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidylinositol (PI), and sphingomyelin (Fig. 2 vi) (Huang, Q. et al., 2019). The host counters HBV's lipid manipulation through multiple defense mechanisms. Sac1, a key phosphatidylinositol phosphatase, disrupts viral propagation by: (i) regulating sphingolipid synthesis to inhibit HBV envelope transport to endosomes (Popescu et al., 2022), and (ii) promoting autophagosome-lysosome fusion to enhance viral particle degradation (Zheng, J. et al., 2023). Furthermore, the 68–117 region of HBx-induced mitochondrial permeabilization—a critical step in HBV pathogenesis—depends on cardiolipin remodeling, which is likely modulated by ceruloplasmin (You et al., 2019).

Apolipoprotein hijacking strategies

Recent studies have identified apolipoprotein, particularly apolipoprotein E (ApoE), as crucial mediators in HBV infection. Structural and functional studies demonstrated that ApoE becomes incorporated into HBV envelopes, where it plays three critical roles in viral pathogenesis (Fig. 2 vii): (1) promoting viral particle production by stabilizing envelope structure (Qiao and Luo, 2019), (2) mediating viral entry through interaction with the low-density lipoprotein receptor (LDLR) (Li, Yingying and Luo, 2021), and (3) influencing host susceptibility through genetic polymorphisms (Yin et al., 2010). Clinical correlations indicate that serum ApoE levels strongly associate with chronic HBV progression (Shen, Yueshuang et al., 2015), highlighting its potential as both a prognostic marker and therapeutic target. HBV also manipulates other apolipoproteins: apolipoprotein H (ApoH) specifically binds HBsAg to support viral persistence (Stefas, 2001), whereas the SHBs downregulates ApoAII, altering cholesterol profiles (Wu, Y. et al., 2024).

Recent evidence also indicates HBeAg-dependent regulation of other apolipoproteins. Serum apolipoprotein M (ApoM) levels are elevated in CHB patients and show a positive correlation with HBV DNA load specifically in HBeAg-negative individuals (Shen, T. et al., 2016), suggesting a role for ApoM in HBV-related lipid metabolism and immune modulation. Similarly, reductions in ApoA1, ApoB, ApoC3 and ApoA5 have been observed in CHB patients, and ApoC3 levels display a negative correlation with HBV DNA load in HBeAg-negative individuals (Cui, Y. et al., 2019). These specific correlations in HBeAg-negative patients are particularly noteworthy, as this phase, while often associated with low replication and minimal inflammation, can also include individuals with active disease driven by viral variants. These HBeAg-dependent associations highlight a broader strategy by which HBV fine-tunes the apolipoprotein network not only to optimize viral infectivity and evade immune responses, but also to modulate host lipid metabolism in a genotype/replication-state dependent manner.

These coordinated modifications of apolipoprotein networks enable HBV to optimize viral infectivity, evade immune responses, and reprogram hepatic lipid metabolism. The critical involvement of apolipoproteins in HBV lifecycle suggests promising therapeutic strategies, including targeting the ApoE-LDLR axis and developing apolipoprotein-specific modulators.

Metabolic-clinical intersections: diabetes-HBV synergism and hormonal regulatory networks

The liver plays a central role in maintaining systemic glucose balance, raising a critical question: does HBV infection perturb blood glucose regulation? Emerging evidence confirms that chronic HBV infection disrupts glycemic control through metabolic reprogramming and hepatic injury, contributing to an elevated prevalence of impaired fasting glucose (IFG) and diabetes mellitus (DM) in affected individuals (Huang, S.C. and Kao, 2024; Abu Baker et al., 2025). The risk of DM correlates with the severity of HBV-related liver disease, exhibiting a hierarchical prevalence: HBV-related cirrhosis (highest risk), chronic HBV infection (average risk), HBV carriers (lowest risk) (Shen, Y. et al., 2017). Notably, prolonged infection duration and high viral load are independent risk factors for DM development (Shen, Yi et al., 2015). In HBV-infected individuals with diabetes, glycemic control is often inadequate. Nonetheless, concomitant antiviral and antidiabetic treatment may improve outcomes (Liu, Q. et al., 2025). These findings underscore the importance of regular dysglycemia screening—particularly oral glucose tolerance tests (OGTT) —in CHB patients (Mavrogiannaki et al., 2009), as tight glycemic control may improve clinical outcomes in this population (Mak et al., 2023).

HBV interferes with key glucose-regulating hormones, creating a bidirectional interplay between viral activity and metabolic dysregulation. HBx has been implicated in the development of insulin resistance and appears to modulate insulin signaling pathways (Kim, H. Y. et al., 2012). HBV infection upregulates intracellular insulin receptors while downregulating functional cell-surface receptors, impairing insulin binding and exacerbating peripheral insulin resistance. This receptor redistribution elevates circulating glucose levels, fostering a pro-diabetic milieu (Barthel et al., 2016). On the other hand, the SHBs activates glucagon, upregulating hepatic gluconeogenesis and further destabilizing glucose homeostasis (Chen, Y. et al., 2022). In addition to these two hormones, glucocorticoids (GCs) further amplify metabolic dysregulation in HBV infection. GCs are steroid hormones that promote liver gluconeogenesis (Kuo et al., 2015). Notably, GCs have been shown to increase the risk of HBV reactivation in patients with rheumatoid arthritis, asthma, and chronic obstructive pulmonary disease (COPD) with prolonged use (Kim, T.W. et al., 2010; Chen, M.H. et al., 2017). This dual role—both as metabolic disruptors and viral reactivation triggers—highlights the complex interplay between HBV, GCs, and host metabolism. When combined with interferon, GCs restore the antiviral efficacy of interferon by restoring signal transducers and activators of transcription methylation (Bing et al., 2014). This highlights context-dependent roles of GCs in HBV management.

HBV infection establishes a vicious cycle of metabolic dysregulation and hepatic dysfunction, driving dysglycemia and accelerating disease progression. Deciphering the hormone-virus-metabolism axis offers novel avenues for improving both virological and metabolic outcomes in CHB patients.

Conclusions and perspectives

The interplay between HBV infection and host cell metabolism presents a promising avenue for therapeutic intervention. Accumulating evidence underscores the genotype-specific modulation of metabolic pathways, particularly through HBx and polymerase rt269 polymorphisms (Lee et al., 2019; Choi et al., 2023; Schollmeier et al., 2024; Zhang, M. et al., 2025). Variations in HBx and polymerase rt269 polymorphisms shape distinct metabolic outcomes: rt269I induces mitochondrial stress and IFN-I signaling, while rt269L promotes HBx stability and autophagy. Similarly, HBV subtypes A1 and A2 differ in replication due to HBx polymorphisms affecting protein stability and structure. These genotype-dependent traits influence mitophagy, ROS production, and mitochondrial integrity, contributing to divergent clinical outcomes. Beyond genotype-specific effects, HBV manipulates key metabolic pathways, such as glycolysis, and FA oxidation, to favor its replication and persistence. Targeting virus-induced metabolic alterations—such as inhibiting hexokinase or acetyl-CoA carboxylase—can disrupt HBV replication and reduce viral load. Additionally, modulating regulator of cellular energetics, such as AMPK, not only restricts viral propagation but also amplifies the host cell's intrinsic antiviral defenses. Notably, cholesterol metabolism constitutes another critical vulnerability in HBV's life cycle, as the virus exploits cholesterol-rich microdomains in host membranes for virion assembly, entry, and secretion. Therapeutic strategies targeting cholesterol homeostasis-such as depleting plasma membrane cholesterol or modulating cholesterol derivatives (e.g., oxysterols), could destabilize HBV's structural integrity and impair its infectivity. These metabolic interventions offer dual benefits: direct antiviral effects and improved metabolic fitness of infected hepatocytes, addressing both viral burden and associated metabolic dysregulation.

Despite these insights, current HBV therapies primarily rely on interferon and nucleoside analogues. Targeting metabolism to enhance treatment is a promising direction for future research. Metabolic targeting holds promise but is hindered by gaps in mechanistic understanding, largely due to limitations in existing models. First, conventional in vitro systems lack the architectural and cellular complexity of native liver tissue, particularly in modeling the dynamic interplay between hepatocytes and non-parenchymal cells. Second, while humanized chimeric mice represent an advance over cell culture systems, they incompletely reproduce the full spectrum of human viral kinetics and immunological responses observed in natural infection. These limitations warrant cautious interpretation of current findings and highlight the need to address several key unanswered questions, including: (i) What mechanisms underlie the apparent protective association between chronic HBV infection and MASLD—does HBV directly suppress lipogenic pathways or act indirectly through immune modulation? (ii) To what extent does virus-induced metabolic reprogramming (e.g., enhanced glycolysis, reduced β-oxidation) drive liver disease progression such as fibrosis or HCC (iii) How do systemic metabolic disorders (e.g., diabetes, obesity) interact with HBV infection and influence viral pathogenesis or therapy responses? (iv) Can nutritional or dietary interventions (e.g., ketogenic or intermittent fasting) modulate HBV-induced metabolic changes and thereby exert antiviral benefits? (v) What is the contribution of non-parenchymal liver cells to the metabolic response during HBV infection, and how does intercellular metabolic crosstalk influence viral persistence?

To address these challenges, several promising research directions could be explored: (1) advanced 3D coculture platforms incorporating hepatic stellate cells, Kupffer cells, and liver sinusoidal endothelial cells may better emulate the liver's metabolic microenvironment; (2) next-generation humanized models with reconstituted adaptive immunity could provide more physiologically relevant platforms for studying immune-metabolic-viral interactions; and (3) longitudinal clinical studies combining multi-omics approaches with detailed metabolic phenotyping may help bridge the gap between experimental findings and human pathophysiology. Such integrative approaches may achieve a more nuanced understanding of how HBV infection intersects with host metabolic pathways, potentially revealing novel therapeutic targets at this critical interface.

Conflict of interest

The authors declare that they have no conflict of interest. Prof. Mengji Lu is an editorial board member for Virologica Sinica and was not involved in the editorial review or the decision to publish this article.