The APOBEC3 family: a narrative review of an alternative therapeutic agent for hepatitis B virus-induced hepatocellular carcinoma

Introduction

Hepatocellular carcinoma (HCC) is one of the deadliest malignancies in the world and arises from a variety of risk factors, including alcohol consumption, viral hepatitis, and genetic predispositions (1). The majority of HCC cases involve underlying cirrhosis, which is the most significant risk factor for this malignancy. Early-stage cirrhosis often presents asymptomatically, complicating its detection. Consequently, patients with HCC with liver-related symptoms are frequently diagnosed at an advanced stage, resulting in a particularly poor prognosis (2). Treatment options for HCC encompass a range of modalities including surgical resection, liver transplantation, ablation techniques, transarterial embolization, radiotherapy, targeted therapies (e.g., sorafenib), and immunotherapies such as immune checkpoint inhibitors. Although significant progress has been made in these treatment approaches, there remains a need for more effective and innovative therapies to improve outcomes for patients with HCC. Ongoing research efforts have been focused on developing novel therapeutic strategies and improving the early detection of HCC to improve patient outcomes (3).

Among the aforementioned pathogenic factors, chronic infection with the hepatitis B virus (HBV) or hepatitis C virus (HCV) are significant contributors to the pathogenesis of HCC, as they can progress to cirrhosis, thereby increasing the likelihood of HCC development (4). HBV can initiate HCC through various mechanisms, including HBV genome integration, HBV-related epigenetic alterations, and the induction of HBV-triggered inflammation. The longer an individual is infected with HBV and HCV, the higher the risk is for HCC. The severity of HCC is correlated with the serum HBV DNA level in patients with chronic hepatitis B (CHB) (5). Recently, two mechanisms have been proposed as being responsible for the development of HBV-related HCC. In the first, HBV genome integration into the host chromosome leads to the suppression of tumor-suppressor genes or the activation of tumor-promoting genes. In the second, HBV-derived factors modulate the expression of specific trans-activators, thereby altering intracellular signal transduction pathways and ultimately regulating host gene expression (6,7). In light of this, effective HBV management is essential to preventing the onset of HCC. Despite the administration of treatments such as vaccines, interferon (IFN), and nucleos(t)ide analogues (NAs) for HBV infections, HBV cannot be completely eradicated (8). Hence, there is an urgent need to develop novel therapeutic agents capable of eradicating HBV and preventing HBV-induced liver cancer.

Within this context, apolipoprotein B messenger RNA editing enzyme catalytic polypeptide-like protein (APOBEC) has emerged as a promising therapeutic candidate for HBV-induced HCC (HBV-HCC), drawing increasing research attention. Its promise stems from several unique attributes: (I) the ability of certain A3 members (e.g., A3A, A3B) to directly target and degrade the persistent covalently closed circular DNA (cccDNA) of HBV—a key reservoir not effectively addressed by current NAs; (II) its dual functional nexus at the intersection of antiviral defense (e.g., inducing viral hypermutation) and tumorigenesis (e.g., editing host genomes), positioning it as a unique node for understanding and intervening in HBV-HCC pathogenesis; and (III) the defined enzymatic domains and regulatory pathways of A3 proteins, which offer clear targets for developing novel small-molecule agonists or inhibitors. The APOBEC family comprises seven subfamilies (A3A, A3B, A3C, A3D, A3F, A3G, and A3H) and is acknowledged to be a natural immune factor that aids the body in combating various viral infections. Previous studies have demonstrated the involvement of the A3 family in catalyzing the deamination of cytidine to uridine in both DNA and RNA (9). In recent years, numerous investigations have reported that within the human innate immune system, the A3 family acts to defend against viral infections, including HBV, HIV, and others. In contrast, the A3 family has also been implicated in tumorigenesis and as exerting a significant influence on the proliferation and advancement of various cancers (9,10).

Although the therapeutic efficacy of the A3 protein in treating HCC has been confirmed, recent research suggests that the A3 family exhibits dual functionality in the context of HBV-HCC. The expression of A3 genes in HBV-infected individuals can induce G-to-A hypermutation within the HBV genome and interact with HBV proteins, thereby impeding the progression of HBV infection toward HCC. However, improper regulation of A3 family deaminase activity may compromise genomic stability, potentially leading to cancer (11-13). The exact role of the A3 family in the HCC environment remains unclear, particularly regarding which aspect of A3 function predominates in the development of HBV-induced liver cancer. We thus conducted a review to consolidate the data on the antiviral role of the A3 family in HBV-HCC treatment and to assess its potential for clinical therapy. We present this article in accordance with the Narrative Review reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1073/rc).

Methods

The following search strategy was employed to focus on HCC, HBV, APOBEC3 protein family, preventive treatment to HBV-HCC (Table 1). We used several terms for our literature search in PubMed and Web of Science. Furthermore, we utilized references that we had used for previous research and publications. We used the following terms and strings of terms: hepatocellular carcinoma, APOBEC3 protein family; hepatitis B virus, APOBEC3 protein family; hepatitis B virus, preventive treatment to HBV-HCC. We limited our selection to those articles that included original research systematic and other types of review articles, and meta-analyses published between 2000 and 2025. We excluded those studies that were not published in English. A total of 108 articles were ultimately identified.

Pathophysiology of HBV-HCC

HBV is a DNA virus with a structure that consists of proteins, a lipid envelope, and an icosahedral nucleocapsid. This core houses the viral genome, which is a partially double-stranded, circular DNA known as relaxed circular DNA (rcDNA) (14). The HBV genome comprises four overlapping open reading frame regions: S, X, C, and P. These regions encode essential viral proteins, including HBV small/medium/large (S/M/L) surface protein (HBs), HBV X protein (HBx), HBV core antigen (HBcAg), and polymerase. HBs form the envelope and serve as antigens, while HBcAg is located in the nucleocapsid core, serving as a marker of viral replication. It is well established that chronic hepatitis, liver cirrhosis, and HCC are intricately linked in a three-step process. Thus, understanding the mechanism underlying the progression of HBV to HCC and the related strategies for HCC prevention are of paramount importance. The following provides a detailed examination of HBV-HCC pathogenesis and the currently available classical treatment approaches (Figure 1).

Figure 1 Diagram of HBV structure and its life cycle when infecting liver cells. (A) HBV’s structure comprises HBsAg, HBeAg, and HBcAg. Within the core particle resides circular and partially double-stranded DNA, along with polymerase enzymes. (B) Schematic illustration of the sequential steps of HBV infection: I, attachment of HBV to host cellular surfaces and subsequent interaction with receptors; II, endocytosis of HBV and fusion with host cells; III, uncoating of HBV and translocation into the nucleus of the host cell; IV, modification of HBV genomic DNA by cellular factors, leading to the formation of rcDNA and subsequent generation of cccDNA; V, transcription of various lengths of viral RNAs with cccDNA serving as a template; VI, translation and synthesis of HBV-related proteins in the ER; VII, self-assembly of HBV components; VIII, budding of HBV from host cells; IX, release of HBV into the extracellular space. cccDNA, covalently closed circular DNA; ER, endoplasmic reticulum; HBcAg, HBV core antigen; HBeAg, HBV soluble E antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; rcDNA, relaxed circular DNA.

Mechanisms of HBV-HCC

HBV significantly influences the carcinogenic process of HCC through both direct and indirect pathways. The immune response mounted by the host during HBV infection can incite liver inflammation, potentially leading to liver fibrosis and cirrhosis. These pathological conditions are often accompanied by heightened turnover of liver cells and the accumulation of mutations. Inherent features of HBV, such as genome instability and the presence of viral proteins, exacerbate liver inflammation. This sustained inflammatory state can disrupt the key signaling pathways involved in inflammation and cancer progression. In turn, this facilitates the increased turnover of liver cells and promotes the accumulation of mutations, thereby advancing the onset and progression of HCC. This induction mechanism is summarized in following sections according to its three primary components.

Insertional mutagenesis and genomic instability of HBV

HBV-HCC exhibits a higher frequency of heterozygosity loss (15), and HBV contributes to genomic instability by integrating viral DNA into the host genome and enabling the activity of viral proteins (16). Prolonged HBV infection and elevated levels of viral replication increase the risk of HCC development. The incidence of liver cirrhosis and HCC is positively and correlated with serum HBV DNA load (17). Whole-genome sequencing has revealed that in cases of HCC, HBV DNA integrates into the genome of hepatocytes at a rate of 80–90%, which is considerably higher than the approximate 30% in non-HCC liver tissues adjacent to HCC. This integration occurs prior to HCC onset (18,19). Generally, a higher number of HBV-DNA integrations, randomly distributed among chromosomes, are detected in HBV-infected livers (20). HBV integration into host cell genes near the insertion site induces instability in the host cell genome, potentially leading to the formation of fusion proteins implicated in carcinogenesis. Studies have demonstrated that all integrated HBV genomes exhibit defects in at least one locus around the cohesive end region, particularly within the HBx gene (21). Moreover, HBV genomic integration is frequently observed in telomerase reverse transcriptase (TERT) loci, with a high clonal ratio (22). TERT, located on chromosome 5p, is directly associated with HBV genome integration (23). It has been noted that 90% of the telomerase is activated in HCC (24). HBV insertion and re-expression of TERT in the TERT promoter may result from wild-type HBx protein and direct transcriptional activation of the TERT promoter by truncated HBx and MHBst proteins, contributing to HBV-related HCC (25).

HBV protein

The second mechanism by which HBV contributes to HCC involves HBV-associated viral proteins. The HBV genome encodes several proteins, including hepatitis B surface antigen (HBsAg), HBcAg, DNA polymerase, and HBx protein. These proteins facilitate HBV genome integration into the host cell genome and influence cell proliferation and viability (26) (Table 2). HBx protein, for instance, is essential for HBV cccDNA replication and enhances HBV carcinogenicity through transcriptional regulation while also directly promoting HCC growth through cell signaling (34). HBcAg has been shown to participate in innate immune responses by binding cccDNA (31,35). Truncated mutants of HBsAg have been linked to increased HBV-associated tumorigenesis, potentially through downregulation of transforming growth factor beta (TGF-β) induced expression related to the TGF-β/SMAD pathway (36). Additionally, HBsAg has been found to enhance the IL-6/STAT3 pathway, further increasing the malignant potential of HBV-associated HCC (37).

Inflammatory response

The inflammatory response also contributes to the development of HBV-HCC. CHB infection progresses through stages of immune tolerance, immune activation, and immune control, with some patients experiencing immune reactivation. Immune-mediated liver injury often leads to elevated levels of alanine aminotransferase (ALT). Additionally, increased levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are commonly observed in the sera of HBV-infected individuals. Chronic liver inflammation, resulting from the host immune response during CHB infection, promotes liver fibrosis, cirrhosis, and HCC progression by accelerating hepatocyte turnover and the accumulation if mutations (38). It is noteworthy that HBV can directly induce HCC without going through the stage of cirrhosis via mechanisms such as integration of viral DNA into the host genome, which differs from the carcinogenic pathway of HCV infection that typically requires cirrhosis. Therefore, when investigating the role of host factors such as the APOBEC3 family in HCC, it is essential to consider their potential differences across distinct pathogenic contexts, such as the presence or absence of cirrhosis.

The progression from chronic HBV infection to HCC is underpinned by a profound and dynamic reprogramming of the host immune system, extending far beyond the initial inflammatory injury. Current research reveals that HBV itself is not directly oncogenic but acts as a critical immunomodulator that lowers the threshold for carcinogenesis. A key mechanism involves the virus amplifying the liver’s response to environmental carcinogens such as diethylnitrosamine. This synergy triggers the release of damage-associated molecular patterns from stressed hepatocytes, which activates the TLR4/TBK1/IRF3 signaling pathway. This cascade culminates in the robust induction of the alarmin cytokine interleukin-33 (IL-33). IL-33 then drives the expansion and activation of ST2-expressing regulatory T cells (Tregs), which establish an immunosuppressive milieu by secreting TGF-β and IL-10, thereby fostering a proneoplastic environment (39). This foundational immunosuppression is perpetuated and intensified within the developing HCC tumor microenvironment (TME), where tumor-associated macrophages (TAMs), predominantly polarized to an M2-like phenotype, emerge as central regulators of immune evasion. TAMs suppress antitumor immunity through multifaceted and synergistic mechanisms. They express immune checkpoint ligands such as programmed death-ligand 1 (PD-L1), which directly engage inhibitory receptors like programmed death 1 (PD-1) and T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) on CD8⁺ T cells to induce functional exhaustion. Furthermore, TAMs deplete critical metabolites, notably L-arginine, via high arginase-1 activity, thereby metabolically starving CD8⁺ T cells and impairing their proliferation and effector functions. Additionally, TAMs contribute to establishing a hypoxic TME, a condition that further promotes T-cell exhaustion and metabolic dysfunction. Collectively, these actions lead to the profound exhaustion of HBV-specific and tumor-reactive CD8⁺ T cells, characterized by a marked loss of cytotoxic potential and cytokine production, which ultimately enables tumor cell survival and proliferation (40). Recent research from Institute of Biophysics, Chinese Academy of Sciences has unveiled more sophisticated mechanisms of immune evasion specific to HBV-HCC. A landmark study in 2025 identified that HBV-related HCC cells exploit the exosome-mediated delivery of a long non-coding RNA, HDAC2-AS2, to directly incapacitate anti-tumor CD8⁺ T cells. The viral HBx protein can activate the TGF-β pathway, which upregulates HDAC2-AS2 in tumor cells. This RNA is then packaged into exosomes and secreted into the TME. Upon uptake by CD8⁺ T cells, HDAC2-AS2 binds to and degrades a key protein called CDK9, which is essential for T cell activation and effector function. This process directly induces CD8⁺ T cell exhaustion and apoptosis, thereby crippling the body’s primary anti-tumor defense force (41).

Furthermore, the dysregulated immune landscape in the chronically inflamed HBV-infected liver creates a permissive context for carcinogenesis. HBV infection itself can modulate the immune response to environmental carcinogens. This highlights a synergistic model where viral infection alters hepatic immunology, lowering the threshold for other oncogenic factors to drive malignant transformation.

Preventive treatment of HBV-HCC

According to the abovementioned information regarding the formation mechanism and etiology of HBV-HCC, it can be concluded that timely intervention for HBV has the potential to effectively mitigate the onset of HCC. Consequently, there has been a surge in research interest on the development of methods that can effectively prevent the HBV infection of liver cells. The commonly used clinical drug preparations are summarized in Table 3.

NAs

The primary mechanism of NAs is the hindrance HBV DNA replication via the targeting of reverse transcriptase. The medications lamivudine, adefovir, and tibivudine have largely fallen out of favor due to the emergence of drug resistance. In contrast, entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide have emerged as the preferred first-line options for anti-HBV therapy (59). Presently, over 80% of patients undergoing antiviral therapy receive NAs. However, these drugs do not directly inhibit the transcriptional activity of cccDNA, thus failing to effectively suppress the expression of viral proteins such as HBsAg. Despite prolonged treatment with NAs, the rate of HBsAg seroconversion remains low, ranging from 0 to 3% (42,43). Moreover, achieving lasting immunological control post-NA treatment is challenging, with a high recurrence rate upon cessation of therapy necessitating long-term or even lifelong medication for the majority of patients (42).

IFNs

IFN exerts its influence on pivotal biological processes including HBV replication and transcription by bolstering immune cell function, stimulating cytokine expression, inducing the production of IFN-stimulated genes (ISGs), and encoding various antiviral proteins through the IFN signaling pathway, thereby serving a dual role in immune regulation and antiviral activity. Moreover, IFN can impede HBV transcription and diminish the expression of viral proteins such as HBsAg by augmenting the degradation of HBV pregenomic RNA (pgRNA) and core particles or through epigenetic modifications of cccDNA (60). In contrast to NAs, IFN therapy is characterized by a limited treatment duration, a heightened serological response, and a prolonged efficacy. Nonetheless, IFN monotherapy demonstrates efficacy only in select patients and is relatively poorly tolerated. For instance, the rate of HBsAg seroconversion following treatment with pegylated IFN-α (PEG-IFN-α) ranges from 3% to 7% (59,61).

Entry inhibitors

Indeed, the entry inhibitor mechanism involves impeding HBV’s entry into liver cells, which is achieved by the inhibitors binding to the receptor sodium taurocholate cotransporting polypeptide (NTCP). NTCP serves as an entry receptor not only for HBV but also for hepatitis D virus (HDV). Several inhibitors are currently available for clinical use, including bulevirtide, hepalatide, and humanized virus-suppressing factor variant (hzVSF). Among these, bulevirtide is one of the most widely used and was approved by the European Union in 2020 for treating chronic HDV infection in adults with HDV RNA-positive compensatory liver disease. Bulevirtide functions by blocking both HBsAg and NTCP. Its antiviral effect stems from its preventing the infection of uninfected hepatocytes and potentially halting the entry of new virions into infected hepatocytes (62,63). However, most studies on bulevirtide have concentrated on chronic HDV infection, and the research on HBsAg clearance is limited (64-66).

Capsid assembly modulators (CAMs)

The HBV core proteins, also known as “capsid proteins”, play a variety of critical roles in the HBV life cycle, making them an attractive target for small-molecule inhibitors. The primary mechanism of action of core inhibitors or CAMs is to hinder HBV replication by disrupting HBV capsid assembly and the encapsulation of pgRNA. CAMs also have secondary mechanisms of action, including inhibiting the establishment of cccDNA by impeding capsid decomposition and obstructing cccDNA recruitment by disrupting the intracellular circulation of HBV nucleocapsid. However, capsid inhibitors have been overshadowed by the downstream NA drugs that have demonstrated significant efficacy in reducing HBV DNA levels, and thus capsid inhibitors are now primarily used when resistance to NAs occur. Additionally, upstream RNA interference (RNAi) drugs can decrease HBsAg levels, whereas nucleocapsid inhibitors typically do not offer a solution for HBsAg reduction (55,56).

The APOBEC3 (A3) family

As previously mentioned, NAs and IFN-α are primary clinical drugs employed in preventive treatment strategies for patients with CHB. However, while NAs effectively hinder HBV replication, they do not act on cccDNA. IFN-α exhibits efficacy in only a small subset of those with CHB and is generally poorly tolerated. Upon hepatocyte infection by HBV, the formation of cccDNA occurs, serving as a template for viral replication. The persistent presence and robust circulation of cccDNA primarily contribute to relapses in patients with chronic viral infections and hinder the achievement of a “functional cure” following drug discontinuation. The clearance of cccDNA serves as a key indicator for the attainment of radical treatment in CHB.

In contrast to NAs and IFN-α, the A3 family comprises a class of cytosine deaminases encompassing seven subfamilies (A3A, A3B, A3C, A3D, A3F, A3G, and A3H), which have implicated as natural immune factors in resisting various viral infections (22). A growing body of evidence suggests that the A3 family influences HBV replication, suppresses HBV transcription, and reduces the levels of viral parameters, including HBsAg, HBV soluble E antigen (HBeAg), and HBcAg, HBV DNA, HBV cccDNA, and HBV RNA, both in vivo and in vitro. Consequently, A3 family members can impede the progression of HBV to HCC (67). Moreover, A3 can influence disease progression through nonmutational pathways, such as immune regulation in the TME. Additionally, alterations induced by A3 include driver mutations that contribute to relapses, affecting oncogenes and tumor suppressors. The A3 family plays a dual role in HBV-HCC, serving as both a biomarker and a potential target for therapy based on clinical associations and preclinical studies. Therefore, investigating the clinical significance of the A3 family in treating HBV-HCC may be a productive direction of research. The following sections describe the A3 family members in detail.

Subunits of the A3 family

The A3 family comprises seven subunits, namely A3A, A3B, A3C, A3D, A3F, A3G, and A3H. Among these, A3A, A3C, and A3H are composed of seven genes, each containing a conserved zinc-coordinating domain, while A3B, A3D, A3F, and A3G possess two domains. Each A3 subunit demonstrates varying degrees of anti-HBV functions. However, further investigation is necessary to comprehensively elucidate the antiviral mechanisms and activities of the A3 family. The known mechanisms and activities of A3 subunits are summarized below, with a partial illustration provided in Figure 2.

Figure 2 The anti-HBV mechanisms of the A3 family. The A3 family of enzymes helps the body defend against viral infections by converting cytidine to uridine in both DNA and RNA. This family has seven subfamilies and is known to protect against viruses, including HBV. When viruses replicate, A3 enzymes cause mutations in their DNA, hindering replication. Additionally, A3 enzymes can reduce the levels of viral elements and may temporarily increase during HBV infection, aiding in viral clearance. cccDNA, covalently closed circular DNA; HBcAg, HBV core antigen; HBeAg, HBV soluble E antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HBxAg, hepatitis B virus X antigen; hnRNP K, heterogeneous ribonucleoprotein K; mRNA, messenger RNA; pgRNA, pregenomic RNA; rcDNA, relaxed circular DNA.

A3A

cccDNA is critical to the genesis and perpetuation of HBV infection, serving both as a template for the synthesis of new viral RNA and progeny viruses, as well as a reservoir for viral recurrence (14). A3A exhibits inhibitory effects on HBV occurrence and progression by targeting cccDNA. Experimental evidence suggests that the heightened expression of A3A cytidine deaminases in HBV-infected cells disrupts the interaction between the HBV core protein and nuclear cccDNA. This disruption leads to cytidine deamination, formation of apurinic/apyrimidinic sites, and consequent degradation of cccDNA, thereby averting HBV reactivation. Additionally, IFN induces cccDNA degradation by promoting the expression of effectors such as A3A, without eliciting cell death (68).

A3B

A3B has been observed to hinder HBV replication by suppressing the synthesis of HBsAg, HBeAg, and HBV core-related DNA (69). Specifically, the A3B protein inhibits the binding of heterogeneous ribonucleoprotein K (hnRNP K) to HBV enhancer II and inhibits HBV S gene transcription. This suggests that the upregulation of A3B can potentially enhance HBV clearance in vivo. Moreover, studies have demonstrated that A3B interacts with the HBV core protein and modifies HBV DNAs during reverse transcription, indicating its multifaceted antiviral effects against HBV (70). A3B selectively edits HBV core-associated DNA but does not affect HBV RNA in wrapped pgRNA and cytoplasm (71). Notably, A3B is unique in its ability to target both transcriptionally active and nontranscriptionally active cccDNAs, leading to cccDNA decay. Therefore, A3B-mediated cccDNA decay could represent a promising therapeutic approach for addressing CHB virus infection (72).

A3C

In contrast to other A3 family members, A3C exhibits relatively little impact on HBV DNA synthesis, and the specific mechanisms by which it interferes with the HBV life cycle remain unclear. Immunoprecipitation assays have revealed there to be a physical interaction between A3C and the HBV core protein (10). Remarkably, A3C primarily induces extensive G-to-A hypermutation of newly synthesized HBV DNA (minus-strand) without causing detectable mutations in HBV DNA. This underscores the high susceptibility of HBV to endogenous human deaminase editing activity and suggests that A3C may contribute to innate anti-HBV host responses (73).

A3D

A3D comprises an N-terminal noncatalytic zinc finger domain and a C-terminal catalytic domain. Although the N-terminal domain is inactive on its own, it enhances the efficiency of the C-terminal enzyme domain (74,75). Unlike other A3 family members, A3D exerts a unique effect by promoting HBV replication through the inhibition of A3F and A3G. Consequently, the upregulation of A3D results in elevated HBV DNA levels (76,77).

A3F

Recently research has revealed that A3F also inhibits HBV DNA levels through G-to-A hypermutation, albeit to a lesser extent. Furthermore, inadequate DNA editing activity of A3F has been observed, indicating that A3F-mediated anti-HBV effects may not be as promising (78). One study reported a physical interaction between A3F and HBV core particles (10).

A3G

A3G is capable of editing approximately 35% of the HBV genome, rendering it the most potent inhibitor of HBV replication currently known. The A3G protein effectively impedes HBV replication and induces a substantial number of G-to-A hypermutations in the replicated HBV genome, thereby reducing HBV DNA expression (79,80). Intriguingly, A3G also exerts regulatory effects on HBV-related proteins. Research by Lei et al. has demonstrated that A3G promotes the clearance of HBeAg and HBsAg (81). Experiments including fluorescence resonance energy transfer methods and surface plasmonic resonance techniques have demonstrated that A3G can be incorporated into HBV particles through direct binding to HBcAg (82). Notably, A3G restricts HBV replication by suppressing viral pgRNA packaging and HBV reverse transcriptase activity within core particles (83,84). The expression of HBcAg from pgRNA facilitates the RNA-dependent recruitment of A3G. However, most A3G proteins associated with HBV core proteins are not encapsidated into complete nucleocapsids due to susceptibility to foreign RNases, thereby restraining viral particle formation to a certain extent (82,85). Other investigations have revealed a synergistic relationship between A3G and IFF, with IFN serving as a direct inducer of A3G (86).

A3H

It has been reported that A3H haplotypes II–VII and splicing variants 183 and 154 exhibit hypermutation activity and contribute to decreased HBV DNA levels (77).

Anti-HBV role of A3 family

As previously mentioned, the A3 family comprises cytosine deaminases that catalyze the conversion of cytidine to uridine in both DNA and RNA (9,87). Although several lines of evidence suggest that dysregulation of the HBV-mediated A3 family may be associated with malignancies, all members of the A3 subfamily inherently possess defenses against both exogenous and endogenous retroviruses, including HBV. During reverse transcription, A3 enzymes deaminate cytidine to uridine within the single-stranded DNA (ssDNA) of the virus, inducing G-to-A hypermutation during second-strand DNA synthesis, thereby impacting HBV replication both in vivo and in vitro. Furthermore, the A3 family can suppress HBV transcription and reduce the levels of viral elements, including HBsAg, HBeAg, HBcAg, HBV DNA, HBV cccDNA, and HBV RNA. Studies have suggested that during HBV infection, the A3 family may undergo temporary upregulation, resulting in the inhibition of HBV genetic replication and the facilitation of viral clearance (88,89) (Figure 2, Table 4).

A3 dysregulation in HCC tumorigenesis

Despite its critical role in anti-HBV defenses, A3 may also drive tumorigenesis due to its genome-mutating functions (9,90,91). Upregulation of A3 genes has been observed in various cancers, with higher A3 expression levels correlating with lower survival rates, particularly in HCC (92,93). The mechanism linking HBV-HCC with the A3 family may involve a viral evolution induced by A3-mediated HBx mutants or mutations within cancer-driving genes edited by A3 deaminases. Given that HBV-induced HCC follows two distinct pathways—“cirrhosis-dependent” and “direct carcinogenesis without cirrhosis”—the role of the A3 family may differ accordingly. In HBV-HCC accompanied by cirrhosis, the sustained inflammatory microenvironment and high hepatocyte turnover may amplify the deaminase activity of A3, making it more likely to induce pro-oncogenic mutations in host genes against a background of pre-existing genomic instability. In non-cirrhotic HBV-HCC, A3 may primarily drive carcinogenesis by editing integrated HBV DNA (e.g., leading to HBx mutant generation) or by directly affecting key host genes. However, further investigation is warranted to clarify the complex interactions between the A3 family and cancer progression. Studies have demonstrated that A3 deaminase edits HBV DNA, leading to the generation of HBx mutants, which in turn enhance colony formation and proliferation of HCC tumor cells (94,95). Interestingly, contradictory findings have been reported, suggesting that A3 deficiency may increase susceptibility to human cancers (96). Investigations into A3 gene expression patterns among tumor and nontumor tissues in patients with HCC have revealed the upregulation of A3B, A3D, A3F, and A3H in tumor tissues compared to nontumor tissues. Specifically, the upregulation of A3G and A3F has been linked to poor survival, while the overexpression of A3C and A3H is associated with favorable survival outcomes (97). Moreover, elevated levels of A3F have been implicated in the increased risk of vascular invasion and intrahepatic metastasis, whereas A3H exhibits the opposite effect. Additional insights into the impact of the A3 family on HCC are provided in Table 5. Given the dual roles of the A3 family in both anti-HBV defense and tumor induction, its involvement in the development of HBV-HCC remains uncertain, and thus further investigation into the underlying mechanisms is warranted.

Potential prophylaxis and treatment strategies related to A3 family for HBV-HCC

As mentioned above, the multifaceted roles of the A3 family, including both restraining HBV activity and contributing to HCC tumorigenesis, suggest two potential strategies for combating HBV-HCC.

First, targeting HBV using A3 proteins entails leveraging their anti-HBV properties across various stages of the HBV life cycle, as elaborated in Section “Anti-HBV role of A3 family”. However, A3 alone proves inadequate for complete HBV virion elimination. Combining A3 with other active factors, such as ISGs, could offer a viable solution. Research indicates that depleting ISG20 attenuates IFN-induced cccDNA loss and that coexpressing it with A3A effectively reduces cccDNA levels in HBV, suggesting potential synergy between ISGs and A3s in anti-HBV activity (102). This relationship in the context of targeting HBV-HCC should be examined further. Moreover, developing precise and low-toxicity drug delivery systems for A3s using advanced materials and assembly technologies is necessary to overcome the inherent limitations of the A3 family, thereby enhancing HBV-HCC treatment.

Second, targeting A3 enzymes directly involves maximizing their anti-HBV effects. Koh et al. pioneered TCR-reprogrammed nonlytic T cells capable of activating A3 in hepatoma cells and HBV-infected human hepatocytes in mice, thereby curbing viral infection with minimal hepatotoxicity (103). These cells hold promise for treating chronic HBV infection and potentially HBV-HCC. Additionally, Chen et al. reported that heat shock protein 90 stimulates A3-mediated DNA deamination activity in vivo, suggesting it has a physiological role in carcinogenesis and viral innate immunity (104). Dysregulation of the A3 family under pathological conditions can have detrimental effects due to improper activity, ultimately leading to HCC. Therefore, targeting aberrant A3 enzyme activity may represent a valuable therapeutic strategy for HBV-HCC. Small-molecule compounds targeting the catalytic pockets of A3s have been reported; for instance, it has been found that 2'-deoxyzebularine analogs selectively inhibit A3B activity and that 5-fluoro-2'-deoxyzebularine is involved in ssDNA’s inhibition of both A3A and A3B (105-107). Despite the promise of A3 inhibitors in treating HBV-HCC, the long-term biological effects of A3 inhibition remain largely unknown. Furthermore, a study by Liu et al. suggested that high-risk HBV mutations may disrupt the balance between A3B and uracil DNA glycosylase (UNG), promoting HCC development, potentially informing specific prophylactic measures against HBV-HCC (101).

Given the dual nature of the A3 family in viral inhibition and tumor induction, understanding their mechanisms and correlations with anti-HBV infection and HBV-HCC is crucial. Although strategies based on the A3 family for HBV-HCC prophylaxis or treatment appear promising, further studies and clinical research are necessary to optimize their efficacy.

Discussion

The multifaceted role of the A3 family in regulating HBV infection and HBV-HCC is complex. Among its seven subunits, mechanisms inhibiting HBV include cccDNA suppression, induction of G-to-A hypermutation, and inhibition of HBV proteins. However, dysregulation of the A3 family by HBV may be linked to malignancies, with the underlying mechanism believed to involve A3-mediated HBx mutants or mutations within cancer-associated genes.

To translate this knowledge into therapeutic strategies, future research must prioritize elucidating the core virological mechanisms of the A3 family against HBV replication. A critical area is understanding how different A3 subtypes target the cccDNA, the viral persistence reservoir. Notably, the epigenetic state of cccDNA governs its susceptibility; transcriptionally repressed cccDNA is less accessible to deaminases like A3A. Furthermore, HBV has evolved a counter-defense mechanism. The viral HBx protein upregulates host heat shock protein B1 (HSPB1), which subsequently reduces the binding of A3A and A3B to cccDNA, thereby enhancing viral persistence. This HBx-HSPB1 axis exemplifies the complex molecular interplay where viral proteins antagonize host restriction factors, extending beyond the well-known interaction between A3G and the HBV core protein. The functional activity of the A3 family is also finely modulated within intricate host cellular networks (108).

A comprehensive understanding also requires delineating the dynamic regulation of A3 expression across the spectrum of HBV infection. Profiling subtype-specific expression in clinical samples from acute to chronic phases will clarify their correlation with viral load and immune status. Since A3 expression is induced by innate immune signaling, such as interferons, its interplay with current therapies like interferon-alpha must be systematically evaluated to identify synergistic or antagonistic effects on cccDNA decay.

Consequently, leveraging the antiviral potency of the A3 family while mitigating their oncogenic risk is a central therapeutic challenge. This oncogenic risk is underscored by evidence that A3 proteins, particularly A3A and A3B, can serve as a physiological mechanism for tumors to acquire a growth advantage through mutagenesis, as observed in other solid malignancies. It is noteworthy, however, that the evidence for a similar role is less consistent for other subunits like A3C and A3H. Promising strategies include developing modalities for the safe, liver-targeted delivery or upregulation of specific antiviral-competent A3 subtypes such as A3A to eliminate cccDNA. In parallel, given the role of A3A and A3B in driving cancer mutagenesis, significant efforts are directed toward developing potent and selective inhibitors. Recent advances have yielded oligonucleotide-based inhibitors with nanomolar potency against A3A and A3G, effectively suppressing their deaminase activity in cells and highlighting a viable path for drug development.

The clinical application of the A3 family in HBV-HCC requires intense evaluation of its associated risks and benefits. Key considerations include the acuity of HBV infection, for which the antiviral efficacy of A3 proteins demonstrates enhanced therapeutic potential during acute-phase viremia. Conversely, in cases of chronic inflammation, A3-mediated mutagenesis of oncogenic drivers (notably TERT promoter and CTNNB1 mutations) may exacerbate TME inflammation through sustained genomic instability. In addition, the selection of subtypes in the A3 family is also crucial, as, for example, A3G is significantly less carcinogenic than A3B.

In summary, given the functional roles of A3 family members in both anti-HBV activities and tumor induction, targeted strategies utilizing the A3 family are recommended. These include developing small-molecule inhibitors that selectively inhibit the A3 carcinogenic domain while retaining its antiviral domain function, which may be a viable strategy. However, addressing the treatment and prognosis of HCC caused by HBV remains a significant clinical challenge. Identifying appropriate targets and functional characteristics of candidate molecules is crucial for the prophylaxis or treatment of HBV-HCC.

Conclusions

The A3 family demonstrates significant antiviral effects against HBV infection. A comprehensive understanding of the underlying mechanisms is essential to elucidating the true relationship between A3 family members, their antiviral effects against HBV, and their involvement in HBV-HCC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1073/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1073/prf

Funding: This study was supported by the Key Program of Zhejiang Provincial Natural Science Foundation of China (No. LZ23H030002); the Special Fund for the Incubation of Young Clinical Scientist, The Children’s Hospital of Zhejiang University School of Medicine (No. CHZJU2022YS003); and the China Postdoctoral Science Foundation (Nos. 2022M720127 and 2024T170798).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1073/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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