---
title: "Viral–Metabolic Interactions and Management Challenges in Chronic Hepatitis B with MAFLD"
id: "frontiers-in-immunology-16-the-viral-metabolic-interaction-mechanisms-and-management-challenges-in-chronic"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-16-the-viral-metabolic-interaction-mechanisms-and-management-challenges-in-chronic"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1920121"
published_at: "2026-08-20T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Viral–Metabolic Interactions and Management Challenges in Chronic Hepatitis B with MAFLD
## Provenance & Clinical Metadata
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- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1920121)
- **Published At:** 2026-08-20T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The provided source is the Frontiers in Immunology listing for an article titled “The ‘viral–metabolic’ interaction mechanisms and management challenges in chronic hepatitis B combined with metabolic dysfunction-associated fatty liver disease: from clinical evidence to an integrated multidisciplinary framework.” - The page content available in the source is site navigation and journal information; the full article text and its clinical details were not included in the provided source. - Because the article body and study data were not present in the source, specific findings, mechanisms, clinical recommendations, study methods, and outcomes are not reported here. - The title indicates the article addresses interactions between **chronic hepatitis B** and **metabolic dysfunction-associated fatty liver disease (MAFLD)**, focusing on **viral–metabolic interaction** mechanisms and management challenges within an integrated multidisciplinary framework. - The article is hosted by Frontiers in Immunology and is categorized under infectious disease/viral immunology, but authorship, methods, evidence synthesis, and conclusions are not available in the provided source. - Readers requiring the article’s detailed clinical evidence, mechanistic summaries, and specific management recommendations should consult the full article at the journal site because those details were not included in the source content.
## Clinical Analysis & Structured Key Points
Frontiers | The “viral–metabolic” interaction mechanisms and management challenges in chronic hepatitis B combined with metabolic dysfunction-associated fatty liver disease: from clinical evidence to an integrated multidisciplinary framework REVIEW article Front. Immunol. , 20 August 2026 Sec. Viral Immunology Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1920121 Published in Frontiers in Immunology Viral Immunology 7 impact factor 11.3 citescore Part of a Research Topic Deciphering host-virus interactions and advancing therapeutics for chronic viral infection: Volume II Submission open 550 views 1 articles Editor & Reviewers Edited by J R Jean-Pierre Routy Reviewed by M A Mirna Aleckovic-Halilovic S K Sania Kouser Outline Figures and Tables Figure 1 View in article Figure 2 View in article Table 1 Summary of research evidence supporting key conclusions in CHB with MASLD. View in article Table 2 Comparison of the virus–metabolism dual-axis dynamic risk management framework with current CHB and MASLD management strategies. View in article Table 3 Virus–metabolism dual-axis dynamic risk stratification and management matrix for CHB with MASLD. View in article REVIEW article Front. Immunol. , 20 August 2026 Sec. Viral Immunology Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1920121 The “viral–metabolic” interaction mechanisms and management challenges in chronic hepatitis B combined with metabolic dysfunction-associated fatty liver disease: from clinical evidence to an integrated multidisciplinary framework Q Z Qianqian Zhu 1,2,3 C S Chengde Su 1,2,3 Q Y Qiaoqiao Yao 1,2,3 T Y Ting Yang 1,2,3 Y X Yali Xu 1,2,3 M L Mingdan Li 1,2,3 Q L Qian Liu 1,2 Y L Yawen Luo 2 P Y Ping Yang 1,2 * 1. Department of Nursing, Affiliated Hospital of Zunyi Medical University, Zunyi, China 2. Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi, China 3. School of Nursing, Zunyi Medical University, Zunyi, China See more Article metrics View details Abstract The comorbidity of chronic hepatitis B and metabolic dysfunction-associated fatty liver disease involves a bidirectional “virus–metabolism” interaction mechanism, presenting a clinical paradox characterized by improved virological markers alongside an increased risk of hepatocellular carcinoma. Therefore, this article aims to systematically review the interaction mechanisms and regulatory factors between the two conditions, and to propose an integrated “virus–metabolism” dual-axis management framework that includes metabolism-stratified antiviral therapy and synchronous metabolic intervention, so as to provide a theoretical basis for stratified management and behavioral intervention of the comorbidity. 1 Introduction Chronic hepatitis B (CHB) and metabolic dysfunction-associated steatotic liver disease (MASLD) represent two major contributors to the global burden of liver disease. With the increasing prevalence of obesity, type 2 diabetes mellitus (T2DM), and changes in dietary patterns worldwide, the burden of MASLD is continuously rising. Epidemiological studies have shown that the prevalence of MASLD reaches approximately 70%, 75%, and 68.8% among individuals with overweight, obesity, and T2DM, respectively, with the prevalence among patients with T2DM in Eastern Europe reaching as high as 80.6% ( 1 ). Meanwhile, CHB remains one of the leading causes of liver-related morbidity and mortality worldwide, particularly in Asia and Africa. When these two highly prevalent liver diseases coexist in the same individual, the coexistence of viral infection and metabolic abnormalities has increasingly become an important clinical issue affecting long-term outcomes in patients with CHB. Previous studies have reported that hepatic steatosis occurs in approximately 32.8% of patients with CHB, with an even higher prevalence of 36.5% among Asian populations ( 2 ). Therefore, patients with CHB combined with MASLD may experience a dual pathological burden resulting from persistent viral infection and metabolic disturbances. Emerging evidence suggests that CHB and MASLD are not simply additive conditions but may involve bidirectional interactions between viral and metabolic pathways. For example, hepatitis B virus (HBV)-encoded X protein (HBx) has been shown to promote lipid accumulation in hepatocytes ( 3 , 4 ), whereas a lipid-rich microenvironment may stabilize HBx expression and impair host immune surveillance ( 5 ). These mechanisms may contribute to an increased risk of hepatocellular carcinoma (HCC) among patients with CHB combined with MASLD ( 6 , 7 ). However, some studies have also observed increased hepatitis B surface antigen (HBsAg) clearance or reduced HBsAg levels in patients with CHB combined with MASLD, suggesting a potential association with improved functional cure outcomes. Notably, this apparent improvement in virological markers does not necessarily translate into reduced clinical risk, as some patients continue to exhibit an elevated risk of HCC development, representing a clinical paradox in which improved viral biomarkers coexist with persistent disease progression risk. Current single-disease management paradigms may not adequately address the long-term management needs of patients with CHB combined with MASLD. Further investigation into the underlying virus–metabolism interactions and their regulatory factors is therefore warranted. Current CHB management guidelines primarily focus on viral suppression, prevention of fibrosis progression, and reduction of HCC risk, whereas stratified management strategies for patients with concomitant metabolic abnormalities remain relatively limited ( 8 , 9 ). Conversely, evidence supporting MASLD management strategies is largely derived from populations without chronic viral hepatitis, and their applicability to patients with CHB has not been fully established ( 10 , 11 ). Consequently, clinical management of patients with CHB combined with MASLD remains challenged by the separation of antiviral management and metabolic intervention, highlighting the need to consider this condition as a complex liver disease entity with distinct pathophysiological characteristics and management requirements. In recent years, substantial progress has been made in understanding the coexistence of CHB and MASLD. Previous reviews have systematically summarized epidemiological characteristics, virus–metabolism interactions, and clinical outcomes associated with this condition ( 8 , 12 , 13 ), providing important insights into the complex relationship between viral infection and metabolic abnormalities. However, existing studies have largely focused on specific mechanisms or individual clinical questions, while systematic integration of how virus–metabolism interactions and immune regulation influence disease management strategies, long-term risk assessment, and modifiable factors remains insufficient. In particular, several aspects require further clarification, including the residual HCC risk under effective virological control, the multilevel factors influencing virus–metabolism balance, and the evidence stratification of different management approaches. Therefore, this review aims to establish a virus–metabolism dual-axis management framework and systematically summarize current evidence from multiple perspectives, including viral mechanisms, immune regulation, metabolic interactions, risk-modifying factors, and clinical management strategies, with the goal of providing a more comprehensive reference for risk assessment and long-term management of patients with CHB combined with MASLD. 2 Virus–metabolism interactions and clinical paradoxes in CHB combined with MASLD 2.1 Clinical characteristics of patients with CHB combined with MASLD Patients with CHB combined with MASLD exhibit substantial clinical heterogeneity. The severity of hepatic steatosis shows a weakened correlation with body mass index (BMI), and significant intrahepatic lipid accumulation may also occur in individuals with normal body weight, suggesting that HBV infection may modify the conventional linear association between metabolic abnormalities and body weight ( 8 ). This observation is consistent with the concept of lean MASLD, which refers to a condition characterized by hepatic steatosis despite a normal BMI. The disease progression risk and long-term outcomes of lean MASLD are comparable to those of non-lean MASLD, and its prevalence is relatively high in Asian populations, which also overlap geographically with regions of high HBV prevalence ( 14 ). These findings suggest that chronic HBV infection may represent a potential contributing factor to the development of lean MASLD. Metabolic abnormalities in patients with CHB combined with MASLD also exhibit phenotypic heterogeneity. Simple hepatic steatosis has been associated with reduced viral load, whereas steatohepatitis accompanied by metabolic syndrome components may shift the predominant disease-driving factors from viral factors toward metabolic factors ( 10 , 12 ). In addition, the interaction between viral infection and metabolic abnormalities appears to be stage-dependent. During the early stage of mild steatosis, metabolic alterations may suppress viral replication through innate immune activation; however, with progression to steatohepatitis, lipotoxicity-related stress responses may synergize with the pro-oncogenic effects of viral proteins and contribute to disease progression ( 15 ). Collectively, the nonlinear metabolic phenotype, heterogeneity of metabolic disturbances, and disease-stage-dependent characteristics collectively contribute to the complexity of managing patients with CHB combined with MASLD, in which bidirectional molecular interactions between viral and metabolic pathways represent an important pathological basis. 2.2 Mechanisms of virus–metabolism interaction and immune regulation in the progression of CHB combined with MASLD 2.2.1 Virus-induced metabolic dysregulation HBV can participate in hepatic lipid metabolic remodeling through multiple viral proteins, among which HBV X protein (HBx) is considered an important regulatory molecule involved in HBV-associated metabolic abnormalities. This mechanism has been repeatedly demonstrated in independent cellular experiments and rodent models. In vitro studies using hepatocyte-derived cell lines have shown that HBx can directly increase the expression of fatty acid transport protein 2 (FATP2) on the hepatocyte membrane. Through the FATP2–long-chain acyl-CoA synthetase 1 (ACSL1) and FATP2–peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways, HBx promotes long-chain fatty acid uptake and intracellular esterification, thereby facilitating triglyceride accumulation in hepatocytes ( 4 , 16 ). In addition, HBx can inhibit the transcriptional activity of PPARα, reduce mitochondrial fatty acid β-oxidation, and further aggravate hepatic lipid accumulation ( 17 , 18 ). Beyond the effects of HBx, cellular studies have demonstrated that excessive synthesis and endoplasmic reticulum retention of hepatitis B surface antigen (HBsAg) can induce the unfolded protein response and activate the sterol regulatory element-binding protein-1c (SREBP-1c) pathway, thereby promoting de novo lipogenesis in hepatocytes ( 19 , 20 ). In addition to directly regulating lipid metabolic pathways, HBV may indirectly disrupt hepatic lipid homeostasis through immunometabolic regulation. Functional in vitro experiments have demonstrated that HBV infection can suppress Toll-like receptor 4 (TLR4)-mediated innate immune responses ( 21 , 22 ) thereby weakening the protective effects of TLR4 signaling against saturated fatty acid-induced lipotoxicity and promoting hepatic lipid accumulation ( 23 ). Furthermore, long-term antiviral therapy may be associated with metabolic abnormalities in some patients. A single-center retrospective clinical study reported that an antiviral treatment duration of more than five years was an independent risk factor for MASLD development among patients with CHB ( 24 ). The underlying mechanisms may involve potential effects of antiviral drugs on lipid metabolism as well as lifestyle changes during prolonged treatment periods, highlighting the importance of metabolic monitoring in patients receiving long-term antiviral therapy ( 25 ). Overall, HBV may contribute to hepatic lipid accumulation and the development of MASLD through multiple mechanisms, including direct regulation by viral proteins, immunometabolic dysregulation, and treatment-related metabolic alterations. 2.2.2 Metabolic feedback regulation of HBV persistence Multiple retrospective cohort studies and systematic reviews have consistently demonstrated that patients with CHB combined with moderate-to-severe MASLD exhibit lower serum HBsAg levels and higher rates of HBsAg seroclearance. This phenomenon has been consistently observed, particularly in Asian cohorts, and represents a relatively well-established clinical characteristic ( 6 , 26 ). However, the molecular mechanisms underlying this observation have not been sufficiently validated in human liver tissues, and current explanations are mainly based on mechanistic hypotheses derived from in vitro studies. At the level of viral protein stability, in vitro cellular experiments have shown that saturated fatty acids can inhibit the ubiquitin–proteasome-mediated degradation of HBx, thereby prolonging its intracellular half-life and enhancing HBV transcriptional activity ( 27 ). Increased HBx stability may not only sustain viral transcription but may also promote immune evasion and persistent antigen stimulation, thereby aggravating host immune dysfunction. Consequently, persistent viral infection and metabolic inflammation may form a mutually reinforcing pathological state. At the level of viral assembly and secretion, cholesterol, as an essential component involved in viral envelope formation, may facilitate HBV particle assembly and secretion when abnormally accumulated within hepatocytes ( 28 ). Based on these in vitro findings, it has been proposed that even when some patients with CHB combined with moderate-to-severe hepatic steatosis exhibit reduced serum HBV DNA levels, active intrahepatic viral replication and viral particle assembly may still persist ( 29 ). Beyond direct effects on HBV itself, metabolic remodeling may indirectly regulate HBV antigen expression and host antiviral immunity through reshaping the intrahepatic immune microenvironment. Cellular and animal studies suggest that persistent hepatic lipotoxic stress can activate TLR4 signaling in Kupffer cells. Importantly, the biological effects of TLR4 activation appear to be highly dependent on disease stage and the surrounding microenvironment. During early infection or transient activation, TLR4-mediated innate immune responses may enhance antiviral immunity and restrict HBV replication. However, under the chronic lipotoxic environment observed in patients with CHB combined with MASLD, sustained TLR4 activation may promote the polarization of Kupffer cells toward a pro-inflammatory phenotype, induce NLRP3 inflammasome activation, and increase the release of pro-inflammatory mediators such as IL-1 β and TNF- α . These processes may contribute to the maintenance of chronic low-grade inflammation and further aggravate hepatic injury and immune dysfunction ( 15 , 30 ). At the adaptive immune level, cellular and animal models have demonstrated that a lipid-rich microenvironment not only promotes regulatory T cell expansion and negatively regulates effector T cell function but also directly affects the metabolic fitness of CD8+T cells. Lipotoxic stress can impair mitochondrial function and glycolytic reprogramming, leading to reduced production of effector molecules and increased expression of immune checkpoint molecules, including PD-1 and TIM-3. These changes may ultimately result in metabolically induced T cell exhaustion and reduced functional antiviral immunity ( 31 ). Furthermore, in vitro transcriptional regulation experiments have shown that abnormal fatty acid activation mediated by long-chain acyl-CoA synthetase 1 (ACSL1) can alter histone acetylation patterns and suppress HBV S gene promoter activity, thereby reducing HBsAg expression ( 32 ). Therefore, the lower HBsAg levels observed in cross-sectional studies among patients with CHB combined with moderate-to-severe hepatic steatosis may reflect the combined effects of metabolic regulation of viral antigen expression and immune exhaustion, rather than indicating true functional clearance of HBV ( 33 ). 2.2.3 Mechanistic basis of virus–metabolism synergy in hepatocarcinogenesis Persistent virus–metabolism interactions may contribute to the remodeling of the hepatic microenvironment toward chronic inflammation, fibrosis, and a pro-tumorigenic state ( 34 ). At the metabolic level, studies using animal models and cellular systems suggest that lipotoxicity-induced oxidative stress and endoplasmic reticulum stress can continuously activate inflammation-related signaling pathways, including JNK and NF-κB. At the viral level, HBV-related proteins may further amplify innate immune inflammatory responses through TLR2/TLR4 signaling ( 35 ). Persistent activation of these pathways may contribute to the establishment of a pro-tumorigenic hepatic microenvironment and facilitate HCC development. Previous studies have demonstrated that HBV DNA integration into the host genome can induce insertional mutagenesis, chromosomal instability, and the formation of virus–host chimeric transcripts, representing important genetic mechanisms involved in HBV-associated hepatocarcinogenesis ( 36 ). Based on these findings from individual mechanistic pathways, it has been proposed that in patients with CHB combined with moderate-to-severe MASLD, metabolic abnormalities-induced oxidative stress may aggravate DNA damage and genomic instability, while HBV integration-related genetic alterations may further amplify chronic inflammatory signaling and abnormal cellular proliferation. Together, these processes may constitute a synergistic pathological basis for hepatocyte malignant transformation. Our previous meta-analysis demonstrated that patients with CHB combined with moderate-to-severe MASLD had a 1.77-fold increased risk of HCC development ( 6 ). This increased risk may be associated with enhanced genomic instability under lipotoxic conditions, persistent activation of JNK/NF-κB signaling, and CD8+T cell dysfunction ( 37 ). In addition, clinical observational studies have shown that patients with this comorbidity frequently exhibit dyslipidemia, particularly elevated small dense low-density lipoprotein cholesterol (sdLDL-C) and reduced high-density lipoprotein cholesterol (HDL-C). These metabolic abnormalities are not only associated with hepatic injury severity but may also indicate increased cardiovascular metabolic risk ( 38 , 39 ). Therefore, CHB combined with moderate-to-severe MASLD should not be considered merely a coexistence of two independent diseases, but rather a complex high-risk condition involving the combined effects of persistent viral infection, lipotoxic injury, immune dysregulation, and metabolic abnormalities. 2.2.4 A systems-level perspective on virus–metabolism–immune interactions in the progression of CHB with MASLD Based on the aforementioned findings from individual mechanistic pathways, this review further proposes a systems-level integrative perspective of virus–metabolism–immune interactions. It should be emphasized that this framework represents a conceptual integration and interpretation of existing evidence rather than an established mechanistic model, and it requires further validation through comprehensive multi-omics studies and prospective clinical cohorts. Previous studies indicate that HBV infection, metabolic abnormalities, and immune dysregulation are
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