Volume 9, Issue 2 (Journal of Clinical and Basic Research (JCBR) 2025)
jcbr 2025, 9(2): 21-27 |
Back to browse issues page
Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Jafari-Sales A, Meskini-Marandi S, Khakpour-Ziaei S, Valipour S, Pashazadeh M. The hidden yet threatening link between hepatitis B virus and hepatocellular carcinoma: A Narrative Review. jcbr 2025; 9 (2) :21-27
URL: http://jcbr.goums.ac.ir/article-1-514-en.html
URL: http://jcbr.goums.ac.ir/article-1-514-en.html
Abolfazl Jafari-Sales1 
, Safa Meskini-Marandi2 , Shabnam Khakpour-Ziaei2 , Sadra Valipour2 , Mehrdad Pashazadeh *3
, Safa Meskini-Marandi2 , Shabnam Khakpour-Ziaei2 , Sadra Valipour2 , Mehrdad Pashazadeh *3
1- Department of Microbiology, Kaz.C., Islamic Azad University, Kazerun, Iran; Infectious Diseases Research Center, TaMS.C., Islamic Azad University of Medical Sciences, Tabriz, Iran
2- Infectious Diseases Research Center, TaMS.C., Islamic Azad University of Medical Sciences, Tabriz, Iran; Department of Cellular and Molecular Biology, Ta.C., Islamic Azad University, Tabriz, Iran
3- Infectious Diseases Research Center, TaMS.C., Islamic Azad University of Medical Sciences, Tabriz, Iran; Department of Medical Laboratory Sciences and Microbiology, TaMS.C., Islamic Azad University, of Medical Sciences, Tabriz, Iran ,mehrdadpashazadeh85@gmail.com
2- Infectious Diseases Research Center, TaMS.C., Islamic Azad University of Medical Sciences, Tabriz, Iran; Department of Cellular and Molecular Biology, Ta.C., Islamic Azad University, Tabriz, Iran
3- Infectious Diseases Research Center, TaMS.C., Islamic Azad University of Medical Sciences, Tabriz, Iran; Department of Medical Laboratory Sciences and Microbiology, TaMS.C., Islamic Azad University, of Medical Sciences, Tabriz, Iran ,
Full-Text [PDF 752 kb]
(97 Downloads)
| Abstract (HTML) (334 Views)
Full-Text: (75 Views)
Introduction
Globally, liver cancer (LC) is the sixth most common cancer diagnosis and the third leading cause of cancer mortality. This has made LC management and diagnosis one of the significant challenges in global health (1,2). Between 2020 and 2040, the number of people with LC is expected to rise by 55% (3). Among the various types of LC, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) are the most common, accounting for 75-85% and 10-15% of LC cases, respectively (4). Multiple factors can contribute to an increased risk of HCC, including obesity, race, gender (5), age, alcohol and tobacco consumption, diabetes mellitus, liver cirrhosis (6), environmental and genetic factors, exposure to carcinogens such as Aflatoxin B1 (AFB1) (7), metabolic diseases, particularly nonalcoholic fatty liver disease (NAFLD), and viral hepatitis infections (8). The hepatitis B virus (HBV) is recognized as the most common viral carcinogenic agent in the liver (9). Hepatocytes are infected with HBV, which results in a variety of liver disorders such as acute hepatitis B virus (AHB), chronic hepatitis B virus (CHB), liver cirrhosis, and HCC, which accounts for half of all cases of HCC. However, people with CHB have the highest chance of developing HCC (10-12). Various factors play a role in the development of HBV-related HCC, including co-infection with other viruses such as Hepatitis C, Hepatitis D, or human immunodeficiency virus (HIV), virus genotype, the effect of HBV oncoprotein and oncogenic factors, long-term infection, and high viral load (13,14). Given the high prevalence of viral hepatitis and its strong association with HCC occurrence, implementing strategies to prevent viral infection, including vaccination and antiviral treatments, is crucial for managing and improving survival rates of patients with HBV-related HCC (15). HBV is one of the most common viral diseases that can have serious consequences, including HCC. However, the molecular mechanisms involved in HBV-related carcinogenesis are not yet fully understood. Additionally, late diagnosis and treatment resistance in HCC patients pose significant challenges, highlighting the need for control and prevention of HBV infection, especially in high-risk populations. This study discusses the relationship between HBV and HCC and to better understand the pathogenic mechanisms involved in this process. Furthermore, this research seeks to evaluate existing and effective preventive strategies and antiviral treatments for the management and treatment of HCC.
Methods
The important connection between HBV and HCC is examined in this thorough narrative review, which focuses on epidemiological patterns, molecular etiology, and preventative measures. We prioritized high-impact clinical studies, reviews, meta-analyses, and recommendations in our systematic literature search throughout PubMed, Scopus, Web of Science, and Google Scholar, with no time limits until 2025. Eighty relevant papers were chosen for in-depth examination from an initial selection. Important facets of HBV-associated hepatocarcinogenesis are examined in this review, including molecular causes, worldwide epidemiological trends, contemporary diagnostic and preventative techniques, and new issues. The narrative method was used to provide both thorough coverage and in-depth analysis of HBV's intricate function in the development of HCC, as well as to integrate existing information, assess current management paradigms, and highlight research needs. This methodology ensures our review integrates the most current, rigorous evidence to clarify HBV-driven hepatocarcinogenesis and its clinical implications, suggesting a foundation for improved prevention and treatment strategies against this lethal cancer.
Results
Structure and genotype of HBV
HBV, as one of the most major human pathogenic viruses, causes serious infectious diseases that lead to a considerable yearly death rate globally. The virus can spread from mother to child (Vertical transmission), through sexual contact, and by contact with bodily fluids, including blood (16-19). A key feature of this virus is its ability to establish lifelong latent infections in cases of CHB, increasing the risk of disease reactivation and necessitating long-term monitoring and treatment. Thus, it remains a major global health challenge (20,21). The 3.2 kb genome of HBV, a partly double-stranded, enveloped DNA virus, is a member of the hepadnaviridae family (22). The compact HBV genome consists of four open reading frames (ORFs): P (Polymerase), Pre-S/S (Surface), Pre-C/C (Core), and X (23). The largest ORF region, P, encodes the viral polymerase (POL), which provides reverse transcriptase (RT), replication, and RNase H activity for the virus (24,25). The three varieties of surface antigens (HBsAg) that include the surface proteins encoded by the S region are small (S-HBs), medium (M-HBs), and large (L-HBs). These three types correspond to the S, Pre-S2 and S, Pre-S1, Pre-S2, and S regions, respectively. The virus may enter the host cell thanks to these proteins, which are found in the viral envelope (26,27). The hepatitis B core protein (HBc), which forms the viral capsid and is necessary for genome packaging and viral replication, is produced in large part by the C region of the viral genome. Hepatitis B virus e antigen (HBeAg) and other core-related proteins are also encoded by the C region (28). The hepatitis B virus regulatory protein X (HBx), encoded by the X region, is responsible for various functions, including DNA transcription control, virus replication, genetic instability induction, DNA damage repair, modulation of cellular signaling pathways, interaction with host cell proteins, apoptosis inhibition, host immune system modulation, and cancer progression (29-31). HBV has ten genotypes, A to J, with their distribution and subgroups dependent on geographical factors, population migrations, and the virus's evolution (32,33). Each HBV genotype has unique clinical outcomes and treatment responses. HCC pathogenesis is often associated with genotypes B and especially C, which are more prevalent in regions where vertical virus transmission is common, such as Asian countries (34,35). Additionally, concurrent infection with various HBV genotypes and viral evolution can result in the creation of recombinant strains, such as HBV C/D, HBV A/G, and HBV D/E, which are highly significant from a clinical standpoint (36,37). Therefore, determining the viral genotype plays a crucial role in selecting appropriate treatment methods and can help reduce symptoms and improve patient outcomes (38).
Molecular mechanisms of HBV pathogenesis and replication and their effect on the development of HCC
Viral entry and receptor interaction
The interaction between the virus and the cell causes conformational changes in the myristoylated N-terminal Pre-S1 region of L-HB. These changes reveal the virus binding site to the sodium taurocholate co-transporting polypeptide receptor (NTCP), leading to virus attachment and entry into the host cell (39). Both the NTCP receptor and the auxiliary epidermal growth factor receptor (EGFR) are bound by HBV, forming an HBV-NTCP-EGFR complex. The HBV-NTCP-EGFR combination enters the cell more easily and co-localizes intracellularly during infection because EGFR functions as a co-receptor for NTCP (40).
Internalization and intracellular transport
Through clathrin-mediated endocytosis (CME), the complex is internalized. After entry, the virus moves through endolysosomes, late endosomes, or early endosomes (41). The endosome carrying the HBV nucleocapsid -followed by the HBV capsid released into the cytoplasm- is transported to the hepatocyte nucleus via the dynein motor complex along the microtubular network (42,43).
Nuclear entry and formation of cccDNA
Nuclear holes made of certain proteins known as the nuclear pore complex (NPC) allow the HBV genome to reach the nucleus, where it disassembles the viral capsid (44). The very stable covalently closed circular DNA (cccDNA) minichromosome is created inside the hepatocyte nucleus from relaxed circular DNA (rcDNA) (45).
Transcription and translation of viral proteins
Pregenomic RNA (pgRNA) and other mRNAs are among the viral RNAs that are produced using cccDNA as a transcription template (46). The pgRNA transcript and other subgenomic transcripts lead to the translation and production of proteins such as viral surface envelope proteins, core proteins, HBx, and viral POL.
Reverse transcription and viral propagation
After transport to the cytoplasm, pgRNA undergoes reverse transcription by viral POL and is converted back to rcDNA. The newly produced rcDNA is encapsidated by HBc. This nucleocapsid can either be expelled from the infected cell, enabling the infection to spread, or it can receive surface envelope polypeptides through the endoplasmic reticulum (ER) and return to the nucleus to refill the cellular cccDNA population (47).
Mechanisms of hepatocarcinogenesis
HBV plays a role in hepatocyte oncogenesis through direct and indirect mechanisms. The integration of newly produced viral DNA via reverse transcription into the host genome and the effect of viral oncoproteins through processes such as chromosomal instability, genetic mutation induction, apoptosis inhibition, cell proliferation induction, and activation of cancer-related genes are among the most important mechanisms contributing to HCC progression (48,49).
Viral mutations and chronic infection
Chronic infection, the virus’s unique genome structure, and immune pressure from the host can lead to mutations in HBV genes. These changes support viral persistence and promote HCC development (49,50).
HBV proteins and ER stress
HBV proteins such as HBx, L-HB, and S-HB are involved in signaling pathways and can trigger ER stress, contributing to HCC progression (51). Deletion mutations in the Pre-S1 or Pre-S2 gene regions result in mutant L-HB accumulation in the ER, activating ER stress. HBx modulates this stress response by inhibiting apoptosis and altering the host cell cycle (51,52).
Formation of ground glass hepatocytes
The buildup of viral surface proteins in hepatocytes overloads the ER, leading to the appearance of ground glass hepatocytes (GGH)-cells with a uniform, opaque, glassy appearance (51,53).
HBx and anti-apoptotic pathways
HBx increases the expression of anti-apoptotic genes (e.g., Bcl-2) and suppresses pro-apoptotic factors (e.g., Bax). It also elevates cytosolic calcium and inactivates caspase-9 and -3, thereby preventing apoptosis and enhancing HBV replication and cytotoxicity (54,55).
Inhibition of tumor suppressors and immune escape
Furthermore, HBx can directly inhibit tumor suppressor genes such as p53, preventing apoptosis and promoting virus replication and spread (56). Furthermore, the accumulation of epitope changes in HBc and HBe over time as a result of immunological pressure from cytotoxic T lymphocytes (CTLs) diminishes the response to the virus, allowing viral immune escape and, ultimately, the advancement of HCC (50) (Figure 1).
Treatment and prevention strategies for HCC associated with the HBV
Management and treatment of HCC depend on various factors, including the patient's age, tumor characteristics and severity, underlying liver dysfunction, comorbidities, access to medical resources, and location (57). Early diagnosis of HCC is crucial for achieving optimal therapeutic outcomes and improving patient survival rates. Therefore, early detection through monitoring and screening in high-risk populations, such as HBV-infected individuals, is essential for implementing preventive strategies and effectively managing HCC (58). Lifestyle modifications, including avoiding alcohol and smoking, engaging in physical activity, maintaining a healthy diet, and utilizing vaccines and antiviral therapies, are well-established strategies for preventing HCC (59). Among these measures, preventing HBV infection is one of the most critical actions to reduce the global incidence of HCC (60). The risk of HBV infection can be minimized by interrupting transmission pathways through blood donor testing, adherence to aseptic principles, screening pregnant women, using human hepatitis B immunoglobulin, and administering vaccines (61). The hepatitis B vaccine, produced from purified viral surface antigens, stimulates the immune system upon injection and leads to antibody production, significantly reducing the risk of HCC (62,63). Since most HBV transmission occurs from mother to child and the likelihood of developing CHB during infancy or early childhood is 90% higher than in adults, vaccinating newborns and infants plays a key role in preventing HBV infection (64,65). Additionally, antiviral therapies for HBV, including interferon-based drugs (Interferons-INF) with immunomodulatory and antiviral effects and nucleotide analogs (Nucleotide Analogs-NAs/NUC), reduce viral DNA levels in CHB patients. These therapies reduce the chance that liver diseases, including HCC, may worsen and recur (62,66). Common NUC drugs include Lamivudine (LAM), Entecavir (ETV), Adefovir (ADV), Telbivudine (LdT), Tenofovir Disoproxil Fumarate (TDF), and Tenofovir Alafenamide (TAF), while Pegylated Interferon (Peg INF) is among interferon-based therapies (67). Although existing antiviral drugs have significantly advanced disease control, challenges such as limited efficacy, numerous side effects, disease recurrence risks, and the emergence of drug-resistant strains highlight the need for developing newer and more effective therapeutic strategies (68) (Table 1). Targeting HBsAg and reducing its levels is considered one of the main goals in the treatment of CHB infection, as this approach is directly associated with improved viral control and a reduction in disease burden. In this regard, in addition to antiviral drugs, new therapies include immunotherapy with immune checkpoint inhibitors (ICIs), particularly drugs targeting the programmed cell death 1(PD-1)/programmed cell death ligand-1(PD-L1) pathway (69,70). Gene and cell therapy, such as chimeric antigen receptor (CAR-T) cells and T cell receptor (TCR-T) cells targeting HBsAg, are also being developed (71,72). Additionally, mucosal-associated invariant T (MAIT) cells (73) and combination therapy are under investigation to enhance treatment efficacy (74,75). Unfortunately, the majority of HCC cases are discovered at an advanced stage, when there are few and ineffective treatment options available, which leads to a far lower patient survival rate (76).
Globally, liver cancer (LC) is the sixth most common cancer diagnosis and the third leading cause of cancer mortality. This has made LC management and diagnosis one of the significant challenges in global health (1,2). Between 2020 and 2040, the number of people with LC is expected to rise by 55% (3). Among the various types of LC, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) are the most common, accounting for 75-85% and 10-15% of LC cases, respectively (4). Multiple factors can contribute to an increased risk of HCC, including obesity, race, gender (5), age, alcohol and tobacco consumption, diabetes mellitus, liver cirrhosis (6), environmental and genetic factors, exposure to carcinogens such as Aflatoxin B1 (AFB1) (7), metabolic diseases, particularly nonalcoholic fatty liver disease (NAFLD), and viral hepatitis infections (8). The hepatitis B virus (HBV) is recognized as the most common viral carcinogenic agent in the liver (9). Hepatocytes are infected with HBV, which results in a variety of liver disorders such as acute hepatitis B virus (AHB), chronic hepatitis B virus (CHB), liver cirrhosis, and HCC, which accounts for half of all cases of HCC. However, people with CHB have the highest chance of developing HCC (10-12). Various factors play a role in the development of HBV-related HCC, including co-infection with other viruses such as Hepatitis C, Hepatitis D, or human immunodeficiency virus (HIV), virus genotype, the effect of HBV oncoprotein and oncogenic factors, long-term infection, and high viral load (13,14). Given the high prevalence of viral hepatitis and its strong association with HCC occurrence, implementing strategies to prevent viral infection, including vaccination and antiviral treatments, is crucial for managing and improving survival rates of patients with HBV-related HCC (15). HBV is one of the most common viral diseases that can have serious consequences, including HCC. However, the molecular mechanisms involved in HBV-related carcinogenesis are not yet fully understood. Additionally, late diagnosis and treatment resistance in HCC patients pose significant challenges, highlighting the need for control and prevention of HBV infection, especially in high-risk populations. This study discusses the relationship between HBV and HCC and to better understand the pathogenic mechanisms involved in this process. Furthermore, this research seeks to evaluate existing and effective preventive strategies and antiviral treatments for the management and treatment of HCC.
Methods
The important connection between HBV and HCC is examined in this thorough narrative review, which focuses on epidemiological patterns, molecular etiology, and preventative measures. We prioritized high-impact clinical studies, reviews, meta-analyses, and recommendations in our systematic literature search throughout PubMed, Scopus, Web of Science, and Google Scholar, with no time limits until 2025. Eighty relevant papers were chosen for in-depth examination from an initial selection. Important facets of HBV-associated hepatocarcinogenesis are examined in this review, including molecular causes, worldwide epidemiological trends, contemporary diagnostic and preventative techniques, and new issues. The narrative method was used to provide both thorough coverage and in-depth analysis of HBV's intricate function in the development of HCC, as well as to integrate existing information, assess current management paradigms, and highlight research needs. This methodology ensures our review integrates the most current, rigorous evidence to clarify HBV-driven hepatocarcinogenesis and its clinical implications, suggesting a foundation for improved prevention and treatment strategies against this lethal cancer.
Results
Structure and genotype of HBV
HBV, as one of the most major human pathogenic viruses, causes serious infectious diseases that lead to a considerable yearly death rate globally. The virus can spread from mother to child (Vertical transmission), through sexual contact, and by contact with bodily fluids, including blood (16-19). A key feature of this virus is its ability to establish lifelong latent infections in cases of CHB, increasing the risk of disease reactivation and necessitating long-term monitoring and treatment. Thus, it remains a major global health challenge (20,21). The 3.2 kb genome of HBV, a partly double-stranded, enveloped DNA virus, is a member of the hepadnaviridae family (22). The compact HBV genome consists of four open reading frames (ORFs): P (Polymerase), Pre-S/S (Surface), Pre-C/C (Core), and X (23). The largest ORF region, P, encodes the viral polymerase (POL), which provides reverse transcriptase (RT), replication, and RNase H activity for the virus (24,25). The three varieties of surface antigens (HBsAg) that include the surface proteins encoded by the S region are small (S-HBs), medium (M-HBs), and large (L-HBs). These three types correspond to the S, Pre-S2 and S, Pre-S1, Pre-S2, and S regions, respectively. The virus may enter the host cell thanks to these proteins, which are found in the viral envelope (26,27). The hepatitis B core protein (HBc), which forms the viral capsid and is necessary for genome packaging and viral replication, is produced in large part by the C region of the viral genome. Hepatitis B virus e antigen (HBeAg) and other core-related proteins are also encoded by the C region (28). The hepatitis B virus regulatory protein X (HBx), encoded by the X region, is responsible for various functions, including DNA transcription control, virus replication, genetic instability induction, DNA damage repair, modulation of cellular signaling pathways, interaction with host cell proteins, apoptosis inhibition, host immune system modulation, and cancer progression (29-31). HBV has ten genotypes, A to J, with their distribution and subgroups dependent on geographical factors, population migrations, and the virus's evolution (32,33). Each HBV genotype has unique clinical outcomes and treatment responses. HCC pathogenesis is often associated with genotypes B and especially C, which are more prevalent in regions where vertical virus transmission is common, such as Asian countries (34,35). Additionally, concurrent infection with various HBV genotypes and viral evolution can result in the creation of recombinant strains, such as HBV C/D, HBV A/G, and HBV D/E, which are highly significant from a clinical standpoint (36,37). Therefore, determining the viral genotype plays a crucial role in selecting appropriate treatment methods and can help reduce symptoms and improve patient outcomes (38).
Molecular mechanisms of HBV pathogenesis and replication and their effect on the development of HCC
Viral entry and receptor interaction
The interaction between the virus and the cell causes conformational changes in the myristoylated N-terminal Pre-S1 region of L-HB. These changes reveal the virus binding site to the sodium taurocholate co-transporting polypeptide receptor (NTCP), leading to virus attachment and entry into the host cell (39). Both the NTCP receptor and the auxiliary epidermal growth factor receptor (EGFR) are bound by HBV, forming an HBV-NTCP-EGFR complex. The HBV-NTCP-EGFR combination enters the cell more easily and co-localizes intracellularly during infection because EGFR functions as a co-receptor for NTCP (40).
Internalization and intracellular transport
Through clathrin-mediated endocytosis (CME), the complex is internalized. After entry, the virus moves through endolysosomes, late endosomes, or early endosomes (41). The endosome carrying the HBV nucleocapsid -followed by the HBV capsid released into the cytoplasm- is transported to the hepatocyte nucleus via the dynein motor complex along the microtubular network (42,43).
Nuclear entry and formation of cccDNA
Nuclear holes made of certain proteins known as the nuclear pore complex (NPC) allow the HBV genome to reach the nucleus, where it disassembles the viral capsid (44). The very stable covalently closed circular DNA (cccDNA) minichromosome is created inside the hepatocyte nucleus from relaxed circular DNA (rcDNA) (45).
Transcription and translation of viral proteins
Pregenomic RNA (pgRNA) and other mRNAs are among the viral RNAs that are produced using cccDNA as a transcription template (46). The pgRNA transcript and other subgenomic transcripts lead to the translation and production of proteins such as viral surface envelope proteins, core proteins, HBx, and viral POL.
Reverse transcription and viral propagation
After transport to the cytoplasm, pgRNA undergoes reverse transcription by viral POL and is converted back to rcDNA. The newly produced rcDNA is encapsidated by HBc. This nucleocapsid can either be expelled from the infected cell, enabling the infection to spread, or it can receive surface envelope polypeptides through the endoplasmic reticulum (ER) and return to the nucleus to refill the cellular cccDNA population (47).
Mechanisms of hepatocarcinogenesis
HBV plays a role in hepatocyte oncogenesis through direct and indirect mechanisms. The integration of newly produced viral DNA via reverse transcription into the host genome and the effect of viral oncoproteins through processes such as chromosomal instability, genetic mutation induction, apoptosis inhibition, cell proliferation induction, and activation of cancer-related genes are among the most important mechanisms contributing to HCC progression (48,49).
Viral mutations and chronic infection
Chronic infection, the virus’s unique genome structure, and immune pressure from the host can lead to mutations in HBV genes. These changes support viral persistence and promote HCC development (49,50).
HBV proteins and ER stress
HBV proteins such as HBx, L-HB, and S-HB are involved in signaling pathways and can trigger ER stress, contributing to HCC progression (51). Deletion mutations in the Pre-S1 or Pre-S2 gene regions result in mutant L-HB accumulation in the ER, activating ER stress. HBx modulates this stress response by inhibiting apoptosis and altering the host cell cycle (51,52).
Formation of ground glass hepatocytes
The buildup of viral surface proteins in hepatocytes overloads the ER, leading to the appearance of ground glass hepatocytes (GGH)-cells with a uniform, opaque, glassy appearance (51,53).
HBx and anti-apoptotic pathways
HBx increases the expression of anti-apoptotic genes (e.g., Bcl-2) and suppresses pro-apoptotic factors (e.g., Bax). It also elevates cytosolic calcium and inactivates caspase-9 and -3, thereby preventing apoptosis and enhancing HBV replication and cytotoxicity (54,55).
Inhibition of tumor suppressors and immune escape
Furthermore, HBx can directly inhibit tumor suppressor genes such as p53, preventing apoptosis and promoting virus replication and spread (56). Furthermore, the accumulation of epitope changes in HBc and HBe over time as a result of immunological pressure from cytotoxic T lymphocytes (CTLs) diminishes the response to the virus, allowing viral immune escape and, ultimately, the advancement of HCC (50) (Figure 1).
Treatment and prevention strategies for HCC associated with the HBV
Management and treatment of HCC depend on various factors, including the patient's age, tumor characteristics and severity, underlying liver dysfunction, comorbidities, access to medical resources, and location (57). Early diagnosis of HCC is crucial for achieving optimal therapeutic outcomes and improving patient survival rates. Therefore, early detection through monitoring and screening in high-risk populations, such as HBV-infected individuals, is essential for implementing preventive strategies and effectively managing HCC (58). Lifestyle modifications, including avoiding alcohol and smoking, engaging in physical activity, maintaining a healthy diet, and utilizing vaccines and antiviral therapies, are well-established strategies for preventing HCC (59). Among these measures, preventing HBV infection is one of the most critical actions to reduce the global incidence of HCC (60). The risk of HBV infection can be minimized by interrupting transmission pathways through blood donor testing, adherence to aseptic principles, screening pregnant women, using human hepatitis B immunoglobulin, and administering vaccines (61). The hepatitis B vaccine, produced from purified viral surface antigens, stimulates the immune system upon injection and leads to antibody production, significantly reducing the risk of HCC (62,63). Since most HBV transmission occurs from mother to child and the likelihood of developing CHB during infancy or early childhood is 90% higher than in adults, vaccinating newborns and infants plays a key role in preventing HBV infection (64,65). Additionally, antiviral therapies for HBV, including interferon-based drugs (Interferons-INF) with immunomodulatory and antiviral effects and nucleotide analogs (Nucleotide Analogs-NAs/NUC), reduce viral DNA levels in CHB patients. These therapies reduce the chance that liver diseases, including HCC, may worsen and recur (62,66). Common NUC drugs include Lamivudine (LAM), Entecavir (ETV), Adefovir (ADV), Telbivudine (LdT), Tenofovir Disoproxil Fumarate (TDF), and Tenofovir Alafenamide (TAF), while Pegylated Interferon (Peg INF) is among interferon-based therapies (67). Although existing antiviral drugs have significantly advanced disease control, challenges such as limited efficacy, numerous side effects, disease recurrence risks, and the emergence of drug-resistant strains highlight the need for developing newer and more effective therapeutic strategies (68) (Table 1). Targeting HBsAg and reducing its levels is considered one of the main goals in the treatment of CHB infection, as this approach is directly associated with improved viral control and a reduction in disease burden. In this regard, in addition to antiviral drugs, new therapies include immunotherapy with immune checkpoint inhibitors (ICIs), particularly drugs targeting the programmed cell death 1(PD-1)/programmed cell death ligand-1(PD-L1) pathway (69,70). Gene and cell therapy, such as chimeric antigen receptor (CAR-T) cells and T cell receptor (TCR-T) cells targeting HBsAg, are also being developed (71,72). Additionally, mucosal-associated invariant T (MAIT) cells (73) and combination therapy are under investigation to enhance treatment efficacy (74,75). Unfortunately, the majority of HCC cases are discovered at an advanced stage, when there are few and ineffective treatment options available, which leads to a far lower patient survival rate (76).
 Figure 1. Mechanisms of HBV carcinogenesis and replication, the replication cycle and carcinogenesis of HBV begin with the virus entering hepatocytes through the NTCP receptor and the EGFR co-receptor. After entry, the viral nucleocapsid is transported toward the cell nucleus by the dynein microtubule system, and the viral genome enters the nucleus through the NPC. Inside the nucleus, the viral rcDNA is converted to cccDNA, followed by transcription and translation of viral proteins. Following virus replication, HBV is released from the cell, causing the spread of infection. Factors such as genomic mutations and the effect of viral oncoproteins like HBx and L-HB promote HCC progression by activating ER stress, inhibiting hepatocyte apoptosis, and evading the immune system. HBV: Hepatitis B Virus; NTCP: Sodium Taurocholate Co-transporting Polypeptide receptor; EGFR: Epidermal Growth Factor Receptor; NPC: Nuclear Pore Complex. |
|
Table 1. Effect of antiviral drugs on HBV
 |
List of Abbreviations
HCC: Hepatocellular Carcinoma; iCCA: Intrahepatic Cholangiocarcinoma, AFB1: Aflatoxin B1, NAFLD: Nonalcoholic Fatty Liver Disease, HBV: Hepatitis B Virus, AHB: Acute Hepatitis B Virus, CHB: Chronic Hepatitis B Virus, ORF: Open Reading Frame; P: Polymerase; S: Surface; C: Core; POL: Polymerase; RT: Reverse Transcriptase; HBsAg: Hepatitis B Virus surface Antigen; S-HB: Small Hepatitis B Surface Protein; M-HB: Medium Hepatitis B Surface Protein; L-HB: Large Hepatitis B Surface Protein; HBeAg: Hepatitis B Virus-e Antigen; HBx: Hepatitis B virus regulatory protein X; NTCP: Sodium Taurocholate Co-Transporting Polypeptide; EGFR: Epidermal Growth Factor Receptor; NPC: Nuclear Pores Complex; rcDNA: Relaxed Circular DNA; cccDNA: Covalently closed circular DNA; pgRNA: Pregenomic RNA; GGH: Ground Glass Hepatocytes; Bcl-2: B-cell leukemia/lymphoma 2; Bax: Bcl-2-associated X protein; CTL: Cytotoxic T Lymphocytes; INF: Interferons; Nas/ NUC: Nucleotide Analogs; LAM: Lamivudine; ETV: Entecavir; ADV: Adefovir; LdT: Telbivudine; TDF: Tenofovir Disoproxil Fumarate; TAF: Tenofovir Alafenamide; Peg INF: Pegylated Interferon; ICIs: Immune Checkpoint Inhibitors; PD-1: Programmed cell Death 1; PD-L1: Programmed cell Death Ligand-1; CAR-T: Chimeric Antigen Receptor T cell; TCR-T: T Cell Receptor cell; MAIT: Mucosal-Associated Invariant T cell; LC: Liver Cancer.
Conclusion
HBV is recognized as a primary etiological factor in LC, particularly HCC. Chronic HBV infection, especially in neonates and infants, can lead to severe hepatic complications, including chronic inflammation, cirrhosis, and ultimately malignant transformations such as HCC. HBV infection disrupts host cellular mechanisms through complex pathways, including genomic integration into host DNA and oncogenic protein activity, which inhibit apoptosis, induce cell proliferation, trigger genetic mutations, and impair immune responses, collectively creating an inflammatory microenvironment conducive to carcinogenesis. Given the strong association between HBV and HCC progression, vaccination and antiviral therapies remain the most effective preventive and therapeutic strategies for controlling HBV infection and reducing HCC risk. However, challenges such as delayed diagnosis, drug resistance emergence, and the need for more targeted therapies persist as critical barriers in this field. Future research should focus on developing curative HBV strategies (e.g., CRISPR-based therapies), personalized antiviral regimens, and integrated screening programs in low- and middle-income countries (LMICs) to enhance early detection and intervention. Addressing these gaps will be essential for advancing novel therapeutic approaches and improving global HCC outcomes.
Acknowledgement
Not applicable.
Funding sources
Not applicable.
Ethical statement
Not applicable.
Conflicts of interest
The authors declare that they have no competing interests.
Author contributions
Idea: A.J.S, M.P; Data Collection or Processing: A.J.S, S.M.M, S.K.Z, S.V; Writing-Review & Editing: S.M.M, S.K.Z, S.V; Figure design: S.K.Z, S.V; Supervision: A.J.S, M.P. All authors reviewed the results and approved the final version of the manuscript.
Data availability statement
Data sharing is not applicable.
HCC: Hepatocellular Carcinoma; iCCA: Intrahepatic Cholangiocarcinoma, AFB1: Aflatoxin B1, NAFLD: Nonalcoholic Fatty Liver Disease, HBV: Hepatitis B Virus, AHB: Acute Hepatitis B Virus, CHB: Chronic Hepatitis B Virus, ORF: Open Reading Frame; P: Polymerase; S: Surface; C: Core; POL: Polymerase; RT: Reverse Transcriptase; HBsAg: Hepatitis B Virus surface Antigen; S-HB: Small Hepatitis B Surface Protein; M-HB: Medium Hepatitis B Surface Protein; L-HB: Large Hepatitis B Surface Protein; HBeAg: Hepatitis B Virus-e Antigen; HBx: Hepatitis B virus regulatory protein X; NTCP: Sodium Taurocholate Co-Transporting Polypeptide; EGFR: Epidermal Growth Factor Receptor; NPC: Nuclear Pores Complex; rcDNA: Relaxed Circular DNA; cccDNA: Covalently closed circular DNA; pgRNA: Pregenomic RNA; GGH: Ground Glass Hepatocytes; Bcl-2: B-cell leukemia/lymphoma 2; Bax: Bcl-2-associated X protein; CTL: Cytotoxic T Lymphocytes; INF: Interferons; Nas/ NUC: Nucleotide Analogs; LAM: Lamivudine; ETV: Entecavir; ADV: Adefovir; LdT: Telbivudine; TDF: Tenofovir Disoproxil Fumarate; TAF: Tenofovir Alafenamide; Peg INF: Pegylated Interferon; ICIs: Immune Checkpoint Inhibitors; PD-1: Programmed cell Death 1; PD-L1: Programmed cell Death Ligand-1; CAR-T: Chimeric Antigen Receptor T cell; TCR-T: T Cell Receptor cell; MAIT: Mucosal-Associated Invariant T cell; LC: Liver Cancer.
Conclusion
HBV is recognized as a primary etiological factor in LC, particularly HCC. Chronic HBV infection, especially in neonates and infants, can lead to severe hepatic complications, including chronic inflammation, cirrhosis, and ultimately malignant transformations such as HCC. HBV infection disrupts host cellular mechanisms through complex pathways, including genomic integration into host DNA and oncogenic protein activity, which inhibit apoptosis, induce cell proliferation, trigger genetic mutations, and impair immune responses, collectively creating an inflammatory microenvironment conducive to carcinogenesis. Given the strong association between HBV and HCC progression, vaccination and antiviral therapies remain the most effective preventive and therapeutic strategies for controlling HBV infection and reducing HCC risk. However, challenges such as delayed diagnosis, drug resistance emergence, and the need for more targeted therapies persist as critical barriers in this field. Future research should focus on developing curative HBV strategies (e.g., CRISPR-based therapies), personalized antiviral regimens, and integrated screening programs in low- and middle-income countries (LMICs) to enhance early detection and intervention. Addressing these gaps will be essential for advancing novel therapeutic approaches and improving global HCC outcomes.
Acknowledgement
Not applicable.
Funding sources
Not applicable.
Ethical statement
Not applicable.
Conflicts of interest
The authors declare that they have no competing interests.
Author contributions
Idea: A.J.S, M.P; Data Collection or Processing: A.J.S, S.M.M, S.K.Z, S.V; Writing-Review & Editing: S.M.M, S.K.Z, S.V; Figure design: S.K.Z, S.V; Supervision: A.J.S, M.P. All authors reviewed the results and approved the final version of the manuscript.
Data availability statement
Data sharing is not applicable.
Article Type: Review |
Subject:
Microbiology
References
1. Wang J, Qiu K, Zhou S, Gan Y, Jiang K, Wang D, et al. Risk factors for hepatocellular carcinoma: an umbrella review of systematic review and meta-analysis. Ann Med. 2025;57(1):2455539. [View at Publisher] [DOI] [PMID] [Google Scholar]
2. Rayapati D, McGlynn KA, Groopman JD, Kim AK. Environmental exposures and the risk of hepatocellular carcinoma. Hepatol Commun. 2025;9(2):e0627. [View at Publisher] [DOI] [PMID] [Google Scholar]
3. Samanta T, Park JH, Kaipparettu BA. Biosocial Determinants of Health Among Patients with Chronic Liver Disease and Liver Cancer. Cancers. 2025;17(5):844. [View at Publisher] [DOI] [PMID] [Google Scholar]
4. Mazzola S, Vittorietti M, Fruscione S, De Bella DD, Savatteri A, Belluzzo M, et al. Factors Associated with Primary Liver Cancer Survival in a Southern Italian Setting in a Changing Epidemiological Scenario. Cancers. 2024;16(11):2046. [View at Publisher] [DOI] [PMID] [Google Scholar]
5. Huang J, Lok V, Ngai CH, Chu C, Patel HK, Thoguluva Chandraseka V, et al. Disease burden, risk factors, and recent trends of liver cancer: a global country-level analysis. Liver Cancer. 2021;10(4):330-45. [View at Publisher] [DOI] [PMID] [Google Scholar]
6. Israr MA. A Case Report of a Rapid Development of Hepatocellular Carcinoma (HCC) Within Six Months of Hepatitis C Cure in an Individual With Risk Factors. Cureus. 2025;17(2):e79571. [View at Publisher] [DOI] [PMID] [Google Scholar]
7. Lu W, Zheng F, Li Z, Zhou R, Deng L, Xiao W, et al. Association between environmental and socioeconomic risk factors and hepatocellular carcinoma: a meta-analysis. Front Public Health. 2022;10:741490. [View at Publisher] [DOI] [PMID] [Google Scholar]
8. Jiang L, Meng Q, Liu L, Li W. A Comprehensive Review on Molecular Mechanisms, Treatments, and Brief Role of Natural Products in Hepatocellular Cancer. Nat Prod Commun. 2024;19(9):1934578X241284873. [View at Publisher] [DOI] [Google Scholar]
9. Varghese N, Majeed A, Nyalakonda S, Boortalary T, Halegoua-DeMarzio D, Hann H-W. Review of related factors for persistent risk of hepatitis B virus-associated hepatocellular carcinoma. Cancers. 2024;16(4):777. [View at Publisher] [DOI] [PMID] [Google Scholar]
10. Choi W-M, Yip TC-F, Kim WR, Yee LJ, Brooks-Rooney C, Curteis T, et al. Chronic hepatitis B baseline viral load and on-treatment liver cancer risk: A multinational cohort study of HBeAg-positive patients. Hepatology. 2024;80(2):428-39. [View at Publisher] [DOI] [PMID] [Google Scholar]
11. Allweiss L, Dandri M. The role of cccDNA in HBV maintenance. Viruses. 2017;9(6):156. [View at Publisher] [DOI] [PMID] [Google Scholar]
12. Polpichai N, Saowapa S, Danpanichkul P, Chan S-Y, Sierra L, Blagoie J, et al. Beyond the Liver: A Comprehensive Review of Strategies to Prevent Hepatocellular Carcinoma. J Clin Med. 2024;13(22):6770. [View at Publisher] [DOI] [PMID] [Google Scholar]
13. Rizzo GEM, Cabibbo G, Craxi A. Hepatitis B virus-associated hepatocellular carcinoma. Viruses. 2022;14(5):986. [View at Publisher] [DOI] [PMID] [Google Scholar]
14. Ringelhan M, O'Connor T, Protzer U, Heikenwalder M. The direct and indirect roles of HBV in liver cancer: prospective markers for HCC screening and potential therapeutic targets. J Pathol. 2015;235(2):355-67. [View at Publisher] [DOI] [PMID] [Google Scholar]
15. Ashtari S, Pourhoseingholi MA, Sharifian A, Zali MR. Hepatocellular carcinoma in Asia: Prevention strategy and planning. World J Hepato. 2015;7(12):1708. [View at Publisher] [DOI] [PMID] [Google Scholar]
16. Ugbaja SC, Mokoena AT, Mushebenge AG-A, Kumalo HM, Ngcobo M, Gqaleni N. Evaluation of the Potency of Repurposed Antiretrovirals in HBV Therapy: A Narrative Investigation of the Traditional Medicine Alternatives. Int J Mol Sci. 2025;26(4):1523. [View at Publisher] [DOI] [PMID] [Google Scholar]
17. Gómez-Moreno A, Ploss A. Mechanisms of hepatitis B virus cccDNA and minichromosome formation and HBV gene transcription. Viruses. 2024;16(4):609. [View at Publisher] [DOI] [PMID] [Google Scholar]
18. Jafari-Sales A, Khakpour-Ziaei S, Meskini-Marandi S, Pashazadeh M. Impact of hepatitis B and C virus on chronic spontaneous urticaria; potential pathogenic triggers and aggravating factors. J Curr Biomed Rep. 2025. [View at Publisher] [DOI] [Google Scholar]
19. Mirzaei G, Shamsasenjan K, Jafari B, Bagherizadeh Y, Sadafzadeh A, Bannazadeh-Baghi H, et al. Prevalence of HBV and HCV infection in beta-thalassemia major patients of Tabriz city, Iran. New Microbes New Infect. 2021;43:100912. [View at Publisher] [DOI] [PMID] [Google Scholar]
20. De Pauli S, Grando M, Miotti G, Zeppieri M. Hepatitis B virus reactivation in patients treated with monoclonal antibodies. World J Virol. 2024;13(1):88487. [View at Publisher] [DOI] [PMID] [Google Scholar]
21. Shi Y, Zheng M. Hepatitis B virus persistence and reactivation. Bmj. 2020:370:m2200. [View at Publisher] [DOI] [PMID] [Google Scholar]
22. Ringlander J, Rydell GE, Kann M. From the Cytoplasm into the Nucleus-Hepatitis B Virus Travel and Genome Repair. Microorganisms. 2025;13(1):157. [View at Publisher] [DOI] [PMID] [Google Scholar]
23. Mlewa M, Henerico S, Nyawale HA, Mangowi I, Shangali AR, Manisha AM, et al. The pattern change of hepatitis B virus genetic diversity in Northwestern Tanzania. Sci Rep. 2025;15(1):8021. [View at Publisher] [DOI] [PMID] [Google Scholar]
24. Lamontagne RJ, Bagga S, Bouchard MJ. Hepatitis B virus molecular biology and pathogenesis. Hepatoma Res. 2016;2:163-86. [View at Publisher] [DOI] [PMID] [Google Scholar]
25. Neuveut C, Wei Y, Buendia MA. Mechanisms of HBV-related hepatocarcinogenesis. J Hepatol. 2010;52(4):594-604. [View at Publisher] [DOI] [PMID] [Google Scholar]
26. Boonstra A, Sari G. HBV cccDNA: The Molecular Reservoir of Hepatitis B Persistence and Challenges to Achieve Viral Eradication. Biomolecules. 2025;15(1):62. [View at Publisher] [DOI] [PMID] [Google Scholar]
27. Sneller L, Lin C, Price A, Kottilil S, Chua JV. RNA Interference Therapeutics for Chronic Hepatitis B: Progress, Challenges, and Future Prospects. Microorganisms. 2024;12(3):599. [View at Publisher] [DOI] [PMID] [Google Scholar]
28. Wei L, Ploss A. Mechanism of hepatitis B virus cccDNA formation. Viruses. 2021;13(8):1463. [View at Publisher] [DOI] [PMID] [Google Scholar]
29. Tu T, Budzinska MA, Shackel NA, Urban S. HBV DNA integration: molecular mechanisms and clinical implications. Viruses. 2017;9(4):75. [View at Publisher] [DOI] [PMID] [Google Scholar]
30. Geng M, Xin X, Bi L-Q, Zhou L-T, Liu X-H. Molecular mechanism of hepatitis B virus X protein function in hepatocarcinogenesis. World J Gastroenterol. 2015;21(38):10732-8. [View at Publisher] [DOI] [PMID] [Google Scholar]
31. Rawat S, Bouchard MJ. The hepatitis B virus (HBV) HBx protein activates AKT to simultaneously regulate HBV replication and hepatocyte survival. J Virol. 2015;89(2):999-1012. [View at Publisher] [DOI] [PMID] [Google Scholar]
32. Sukowati CH, Jayanti S, Turyadi T, Muljono DH, Tiribelli C. Hepatitis B virus genotypes in precision medicine of hepatitis B-related hepatocellular carcinoma: where we are now. World J Gastrointest Oncol .2024;16(4):1097-1103. [View at Publisher] [DOI] [PMID] [Google Scholar]
33. Castro GM, Sosa MJ, Sicilia PE, Riberi MI, Moreno C, Cattaneo R, et al. Acute and chronic HBV infection in central Argentina: High frequency of sub-genotype F1b, low detection of clinically relevant mutations and first evidence of HDV. Front Med. 2023;9:1057194. [View at Publisher] [DOI] [PMID] [Google Scholar]
34. Chen J, Li L, Yin Q, Shen T. A review of epidemiology and clinical relevance of Hepatitis B virus genotypes and subgenotypes. Clin Res Hepatol Gastroenterol. 2023;47(7):102180. [View at Publisher] [DOI] [PMID] [Google Scholar]
35. Sato K, Inoue J, Akahane T, Kobayashi T, Ninomiya M, Sano A, et al. Comparison of hepatitis B virus genotype B and C patients in Japan in terms of family history and maternal age at birth. Hepatol Res. 2025;55(5):773-9. [View at Publisher] [DOI] [PMID] [Google Scholar]
36. Assefa A, Getie M, Getie B, Yazie TS, Enkobahry A. Molecular epidemiology of hepatitis B virus (HBV) in Ethiopia: a review article. Infect Genet Evol. 2024:122:105618. [View at Publisher] [DOI] [PMID] [Google Scholar]
37. Lin C-L, Kao J-H. Natural history of acute and chronic hepatitis B: the role of HBV genotypes and mutants. Best Pract Res Clin Gastroenterol. 2017;31(3):249-55. [View at Publisher] [DOI] [PMID] [Google Scholar]
38. Raimondi S, Maisonneuve P, Bruno S, Mondelli MU. Is response to antiviral treatment influenced by hepatitis B virus genotype? J Hepatol.
2010;52(3):441-9. [View at Publisher] [DOI] [PMID] [Google Scholar]
39. Van Damme E, Vanhove J, Severyn B, Verschueren L, Pauwels F. The hepatitis B virus interactome: a comprehensive overview. Front Microbiol.
2021;12:724877. [View at Publisher] [DOI] [PMID] [Google Scholar]
40. Ren EC, Zhuo NZ, Goh ZY, Bonne I, Malleret B, Ko HL. cccDNA-Targeted Drug Screen Reveals a Class of Antihistamines as Suppressors of HBV Genome Levels. Biomolecules. 2023;13(10):1438. [View at Publisher] [DOI] [PMID] [Google Scholar]
41. Herrscher C, Roingeard P, Blanchard E. Hepatitis B virus entry into cells. Cells. 2020;9(6):1486. [View at Publisher] [DOI] [PMID] [Google Scholar]
42. Diogo Dias J, Sarica N, Neuveut C. Early steps of hepatitis B life cycle: from capsid nuclear import to cccDNA formation. Viruses. 2021;13(5):757. [View at Publisher] [DOI] [PMID] [Google Scholar]
43. Osseman Q, Gallucci L, Au S, Cazenave C, Berdance E, Blondot M-L, et al. The chaperone dynein LL1 mediates cytoplasmic transport of empty and mature hepatitis B virus capsids. J Hepatol. 2018;68(3):441-8. [View at Publisher] [DOI] [PMID] [Google Scholar]
44. Prange R. Hepatitis B virus movement through the hepatocyte: An update. Biol Cell. 2022;114(12):325-48. [View at Publisher] [DOI] [PMID] [Google Scholar]
45. Tsukuda S, Watashi K. Hepatitis B virus biology and life cycle. Antiviral Res. 2020;182:104925. [View at Publisher] [DOI] [PMID] [Google Scholar]
46. Kaur SP, Talat A, Karimi-Sari H, Grees A, Chen HW, Lau DT, et al. Hepatocellular carcinoma in hepatitis B virus-infected patients and the role of hepatitis B surface antigen (HBsAg). J Clin Med. 2022;11(4):1126. [View at Publisher] [DOI] [PMID] [Google Scholar]
47. D'souza S, Lau KC, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol.
2020;26(38):5759-83. [View at Publisher] [DOI] [PMID] [Google Scholar]
48. Arslan F, Franci G, Maria Nastri B, Pagliano P. Hepatitis B virus-induced hepatocarcinogenesis: A virological and oncological perspective. J Viral Hepat. 2021;28(8):1104-9. [View at Publisher] [DOI] [PMID] [Google Scholar]
49. Elpek GO. Molecular pathways in viral hepatitis-associated liver carcinogenesis: An update. World J Clin Cases. 2021;9(19):4890-917. [View at Publisher] [DOI] [PMID] [Google Scholar]
50. Jiang Y, Han Q, Zhao H, Zhang J. The mechanisms of HBV-induced hepatocellular carcinoma. J Hepatocell Carcinoma. 2021:8:435-50. [View at Publisher] [DOI] [PMID] [Google Scholar]
51. Lin W-L, Hung J-H, Huang W. Association of the hepatitis B virus large surface protein with viral infectivity and endoplasmic reticulum stress-mediated liver carcinogenesis. Cells. 2020;9(9):2052. [View at Publisher] [DOI] [PMID] [Google Scholar]
52. Lin Y-T, Jeng L-B, Chan W-L, Su I-J, Teng C-F. Hepatitis B virus Pre-S gene deletions and Pre-S deleted proteins: clinical and molecular implications in hepatocellular carcinoma. Viruses. 2021;13(5):862. [View at Publisher] [DOI] [PMID] [Google Scholar]
53. Li Y, Xia Y, Cheng X, Kleiner DE, Hewitt SM, Sproch J, et al. Hepatitis B surface antigen activates unfolded protein response in forming ground glass hepatocytes of chronic hepatitis B. Viruses. 2019;11(4):386. [View at Publisher] [DOI] [PMID] [Google Scholar]
54. Zhang T-Y, Chen H-Y, Cao J-L, Xiong H-L, Mo X-B, Li T-L, et al. Structural and functional analyses of hepatitis B virus X protein BH3-like domain and Bcl-xL interaction. Nat Commun. 2019;10(1):3192. [View at Publisher] [DOI] [PMID] [Google Scholar]
55. Yao J, Guo J, Xie Y. Hepatitis B virus induced cirrhosis and hepatocarcinoma: pathogenesis and therapeutics. Explor Dig Dis. 2025;4:100565. [View at Publisher] [DOI] [Google Scholar]
56. Kim S, Park J, Han J, Jang KL. Hepatitis B Virus X Protein Induces Reactive Oxygen Species Generation via Activation of p53 in Human Hepatoma Cells. Biomolecules. 2024;14(10):1201. [View at Publisher] [DOI] [PMID] [Google Scholar]
57. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589-604. [View at Publisher] [DOI] [PMID] [Google Scholar]
58. Xu Y, Xia C, Li H, Cao M, Yang F, Li Q, et al. Survey of hepatitis B virus infection for liver cancer screening in China: A population-based, cross-sectional study. Chin Med J. 2024;137(12):1414-20. [View at Publisher] [DOI] [PMID] [Google Scholar]
59. Zelber-Sagi S, Noureddin M, Shibolet O. Lifestyle and hepatocellular carcinoma what is the evidence and prevention recommendations. Cancers. 2021;14(1):103. [View at Publisher] [DOI] [PMID] [Google Scholar]
60. Mak L-Y, Cruz-Ramón V, Chinchilla-López P, Torres HA, LoConte NK, Rice JP, et al. Global epidemiology, prevention, and management of hepatocellular carcinoma. Am Soc Clin Oncol Educ Book. 2018;38(38):262-79. [View at Publisher] [DOI] [PMID] [Google Scholar]
61. Franco E, Bagnato B, Marino MG, Meleleo C, Serino L, Zaratti L. Hepatitis B: Epidemiology and prevention in developing countries. World J Hepatol. 2012;4(3):74-80. [View at Publisher] [DOI] [PMID] [Google Scholar]
62. Zhang X, Guan L, Tian H, Zeng Z, Chen J, Huang D, et al. Risk factors and prevention of viral hepatitis-related hepatocellular carcinoma. Front Oncol.
2021;11:686962. [View at Publisher] [DOI] [PMID] [Google Scholar]
63. Addissouky TA, Sayed IETE, Ali MM, Wang Y, Baz AE, Khalil AA, et al. Latest advances in hepatocellular carcinoma management and prevention through advanced technologies. Egypt Liver J. 2024;14(1):2. [View at Publisher] [DOI] [Google Scholar]
64. Pattyn J, Hendrickx G, Vorsters A, Van Damme P. Hepatitis B vaccines. J Infect Dis. 2021;224(Supplement_4):S343-S51. [View at Publisher] [DOI] [PMID] [Google Scholar]
65. Morgan HJ, Nold MF, Kattan GS, Vlasenko D, Malhotra A, Boyd JH, et al. Hepatitis B vaccination of preterm infants and risk of bronchopulmonary dysplasia: a cohort study, Australia. Bull World Health Organ. 2025;103(3):187-93. [View at Publisher] [DOI] [PMID] [Google Scholar]
66. Kim SK, Fujii T, Kim SR, Nakai A, Lim Y-S, Hagiwara S, et al. Hepatitis B virus treatment and hepatocellular carcinoma: controversies and approaches to consensus. Liver Cancer. 2022;11(6):497-510. [View at Publisher] [DOI] [PMID] [Google Scholar]
67. Chien R-N, Liaw Y-F. Current trend in antiviral therapy for chronic hepatitis B. Viruses. 2022;14(2):434. [View at Publisher] [DOI] [PMID] [Google Scholar]
68. Pisano MB, Giadans CG, Flichman DM, Ré VE, Preciado MV, Valva P. Viral hepatitis update: Progress and perspectives. World J Gastroenterol.
2021;27(26):4018-44. [View at Publisher] [DOI] [PMID] [Google Scholar]
69. Mon H-C, Lee P-C, Hung Y-P, Hung Y-W, Wu C-J, Lee C-J, et al. Functional cure of hepatitis B in patients with cancer undergoing immune checkpoint inhibitor therapy. J Hepatol. 2025;82(1):51-61. [View at Publisher] [DOI] [PMID] [Google Scholar]
70. Cao W-H, Zhang Y-Q, Li X-X, Zhang Z-Y, Li M-H. Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients. World J Hepatol. 2024;16(10):1158-68. [View at Publisher] [DOI] [PMID] [Google Scholar]
71. Zou F, Tan J, Liu T, Liu B, Tang Y, Zhang H, et al. The CD39+ HBV surface protein-targeted CAR-T and personalized tumor-reactive CD8+ T cells exhibit potent anti-HCC activity. Mol Ther. 2021;29(5):1794-807. [View at Publisher] [DOI] [PMID] [Google Scholar]
72. Tan AT, Hang SK, Tan N, Krishnamoorthy TL, Chow WC, Wong RW, et al. A rapid method to assess the in vivo multi-functionality of adoptively transferred engineered TCR T cells. Immunother Adv. 2024;4(1):ltae007. [View at Publisher] [DOI] [PMID] [Google Scholar]
73. Healy K, Pavesi A, Parrot T, Sobkowiak MJ, Reinsbach SE, Davanian H, et al. Human MAIT cells endowed with HBV specificity are cytotoxic and migrate towards HBV-HCC while retaining antimicrobial functions. JHEP Rep. 2021;3(4):100318. [View at Publisher] [DOI] [PMID] [Google Scholar]
74. Huang D, Ke L, Cui H, Li S. Efficacy and safety of PD-1/PD-L1 inhibitors combined with anti-angiogenic therapy for the unresectable hepatocellular carcinoma and the benefit for hepatitis B virus etiology subgroup: a systematic review and meta-analysis of randomized controlled trials. BMC Cancer. 2023;23(1):474. [View at Publisher] [DOI] [PMID] [Google Scholar]
75. Qin A, Ho M-C, Tsai C-Y, Liu C-J, Chen P-J. Sequential combination with ropeginterferon alfa-2b and anti-PD-1 treatment as adjuvant therapy in HBV-related HCC: a phase 1 dose escalation trial. Hepatol Int. 2025;19(3):547-59. [View at Publisher] [DOI] [PMID] [Google Scholar]
76. Deng LX, Mehta N. Does hepatocellular carcinoma surveillance increase survival in at-risk populations? Patient selection, biomarkers, and barriers. Dig Dis Sci. 2020;65(12):3456-62. [View at Publisher] [DOI] [PMID] [Google Scholar]
77. Hu Y, Zhang Y, Jiang W. Targeting hepatitis B virus-associated nephropathy: efficacy and challenges of current antiviral treatments .Clin Exp Med.
2025;25(1):57. [View at Publisher] [DOI] [PMID] [Google Scholar]
78. Woo ASJ, Kwok R, Ahmed T. Alpha-interferon treatment in hepatitis B. Ann Transl Med. 2017;5(7):159. [View at Publisher] [DOI] [PMID] [Google Scholar]
79. Koumbi L. Current and future antiviral drug therapies of hepatitis B chronic infection. World J Hepatol. 2015;7(8):1030-40. [View at Publisher] [DOI] [PMID] [Google Scholar]
80. Kayaaslan B, Guner R. Adverse effects of oral antiviral therapy in chronic hepatitis B. World J Hepatol. 2017;9(5):227-41. [View at Publisher] [DOI] [PMID] [Google Scholar]
Send email to the article author
| Rights and permissions | |
 |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0).