The family of Signal Transducer and Activator of Transcription (STAT) proteins, which includes STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6, functions as cytoplasmic transcription factors that mediate various intracellular signaling pathways. Notably, STAT3 plays a pivotal role in several biological processes, including cell proliferation, survival, differentiation, and angiogenesis (Zou et al., 2020).

According to the canonical mechanism, inactive STAT3 resides in the cytoplasm. Upon stimulation by growth factors, cytokines, hormones, or other oncogenic proteins, the upstream proteins subsequently induce the phosphorylation of STAT3 at tyrosine 705 (Y705) and serine 727 (S727) residues in the C-terminal transactivation domain (Wang et al., 2024). This phosphorylation triggers STAT3 dimerization and subsequent nuclear translocation. In the nucleus, STAT3 binds to DNA to promote transcription of target genes (Chen et al., 2023).

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, is capable of initiating caspase-8-dependent apoptosis in transformed cells, inducing apoptosis in a broad range of cancer cells (Lv et al., 2025a). Significantly, it achieves this without causing fatality in essential normal cells. This process is triggered through its binding and subsequent activation of two specific receptors: TRAIL-Receptor1 (TRAIL-R1) and TRAIL-R2 (Lv et al., 2025a), whereas TRAIL-R3 can inhibit TRAIL-induced apoptosis by competing with TRAIL for binding to death receptors such as TRAIL-R2 (Degli-Esposti et al., 1997). TRAIL plays a significant role in inhibiting HBV. TRAIL not only inhibited HBV replication via blocking DNA synthesis (Suehiro et al., 2023), but also suppressed the proliferation of autoreactive T-cells by inhibiting the production of IL-2, IL-4, and INF-γ, impeding cell cycle progression from the G1 phase to the S phase and restricting calcium influx (Koliaki and Katsilambros, 2022). In the inflamed HBV-infected liver, the notable presence of activated NK cells with elevated TRAIL levels could serve a dual purpose. On the one hand, while it is true that this mechanism may contribute to the death of hepatocytes infected with HBV, it can also result in non-specific damage to hepatocytes and exacerbate liver inflammation. On the other hand, it facilitates the apoptosis of T cells that express elevated TRAIL receptors. This process could potentially result in the depletion of HBV-specific T cells and compromise the immune system’s ability to eliminate HBV (Peppa et al., 2013). This apoptotic process requires the participation of TRAIL-R2. In HBV infection, HBV-specific CD8⁺T cells, especially those infiltrating the liver, overexpress the TRAIL-R2 death-inducing receptor, thereby delivering an apoptotic signal (Peppa et al., 2013). The upregulation of TRAIL-R2 expression can predispose cells to apoptosis triggered by TRAIL, through receptor-ligand interactions and subsequent signal transduction pathways. Besides TRAIL-R2, the HBV (HBx) influences TRAIL-R3 transcription via the activation of NF-κb signaling pathway. An increase in TRAIL-R3 can impede TRAIL-dependent apoptosis and TRAIL-mediated HBV replication inhibition within HBV-infected liver cells (Suehiro et al., 2023).

TRAIL may suppress autoimmune diseases by downregulating immune responses (Cardoso Alves et al., 2021), whereas TRAIL deficiency exacerbates autoimmune diabetes and enhances autoimmune responses, as demonstrated by experimental observations (Lamhamedi-Cherradi et al., 2003). TRAIL exerts its function by suppressing IL-2 production and cell cycle progression, thereby inhibiting the proliferation of diabetogenic T-cells in nonobese diabetic mice during the development of autoimmune type 1 diabetes (Mi et al., 2003). TRAIL inhibits pancreatic β-cell apoptosis in type 1 diabetes mellitus by enhancing tissue inhibitor of metalloproteinase 1 function. This mechanism may reduce matrix metalloproteinase activity (Fogarasi and Dima, 2024). Following TRAIL overexpression, subsequent protein kinase B (Akt/PKB) activation stimulates β-cell proliferation, ultimately producing an anti-diabetic effect that is associated with increased SOCS1 expression (Koliaki and Katsilambros, 2022; Fogarasi and Dima, 2024). In T2DM, TRAIL demonstrates beneficial effects through its immunosuppressive and immunoregulatory properties, which mitigate the chronic inflammation characteristic of T2DM. It exhibits proliferative action on the beta-cell mass of pancreatic islets, insulin-sensitizing and myogenic action on skeletal muscle tissue, and hepatoprotective action, mainly improvement of non-alcoholic fatty liver disease (NAFLD) (Koliaki and Katsilambros, 2022).

In summary, TRAIL represents a critical molecular nexus between hepatotropic viral infections and diabetes. It modulates the progression of HBV infection through immunoregulation and apoptosis control, while concurrently demonstrating pleiotropic effects in glucose metabolism and immune homeostasis. These dual properties position TRAIL as a promising therapeutic target for both disease entities. However, the mechanistic complexity of TRAIL signaling necessitates further rigorous investigation to optimize its therapeutic potential while mitigating potential adverse effects.

Endoplasmic reticulum (ER) stress refers to the cellular response when faced with various stresses or stimuli, characterized by the accumulation of misfolded and unfolded proteins within the ER lumen, as well as the disruption of calcium ion balance, which will happen in HBV-infected cells (Soh et al., 2024; Ghionescu et al., 2025). The HBx triggers ER stress through multiple mechanisms, including cellular ATP depletion, upregulated stromal cell-derived factor-1 expression, and exacerbated hepatic lipid accumulation, collectively enhancing autophagosome formation to facilitate viral replication and envelopment (Hu et al., 2022; Wang et al., 2022). Similarly, HCV infection elevates ER stress by impairing calcium regulation. Viral gene expression augments mitochondrial reactive oxygen species (ROS) production through calcium-dependent signaling pathways (Tardif et al., 2005). This oxidative stress in the liver is upregulated by not only the core nucleocapsid protein of HCV, but also other proteins such as NS3, NS5A, and NS5B (Martin de Fourchambault et al., 2023). The HCV nonstructural proteins NS3 through NS5B coordinate viral replication through formation of a ribonucleoprotein complex associated with ER-derived membranous webs, a process that can induce ER stress (Tardif et al., 2005). Notably, NS5A specifically activates both NF-κB and STAT-3 through mechanisms requiring coordinated Ca2⁺ signaling and reactive oxygen species (ROS) production from ER-mitochondrial crosstalk (Gong et al., 2001). Mitochondria and ER networks maintain intricate junctions, termed mitochondria-associated ER membranes (MAMs), which are instrumental in Ca2+ signaling, lipid trafficking, energy metabolism, and cell survival. However, in the process of hepatitis virus self-replicating and damaging host cells, it also destroys the MAMs by producing ER stress. MAMs represent a novel site for insulin-stimulated PKB/Akt phosphorylation. Compromised MAM integrity may impair insulin signaling pathways (including Akt/PKB activation) and disrupt glucose/lipid homeostasis, ultimately contributing to hepatic insulin resistance (IR). This mechanistic link suggests that hepatitis viruses may induce IR through oxidative stress-mediated MAM dysfunction (Tubbs et al., 2014). The pathways through which hepatitis virus-mediated ER stress may contribute to the development of diabetes are illustrated in the figure below ( Figure 2 ).

Akt/PKB protein kinase B, ER endoplasmic reticulum, MAMs mitochondria-associated ER membranes, NF-κB nuclear factor kappa-B, HBs hepatitis B surface antigen, HBV hepatitis B virus, HCV hepatitis C virus, ROS reactive oxygen species.

In addition to ER stress, hepatitis viruses can also mediate oxidative stress and cause inflammation through Nox. In HBV infection, clinical observations demonstrate significant reductions in serum glutathione and superoxide dismutase levels (Yang et al., 2020). The resulting HBV-induced ROS accumulation promotes hepatic inflammation through IL-6 upregulation in hepatocellular carcinoma (HCC), concurrently driving constitutive STAT3 activation. Regarding HCV, the NS3 protein activates NADPH oxidase, which may contribute to the natural progression of hepatitis C infection (Matuz-Mares et al., 2022). Additionally, HCV infection induces sustained upregulation of Nox1/4, with Nox4 showing increased nuclear localization in both in vitro models and human liver tissues. These findings identify Nox1/4 as persistent endogenous ROS source during HCV pathogenesis (de Mochel et al., 2010). NOX overexpression under pathological conditions mediates ROS generation, commonly termed oxidative burst (Sandoval et al., 2018). This process activates multiple pathogenic pathways, including aldose reductase, advanced glycation end product formation, protein kinase C signaling, and hexosamine flux. Concurrently, it stimulates pro-inflammatory cytokines (TGF-β, TNF-α, NF-κB, IL-6, IL-18), endothelial growth factor production, hyperlipidemia development, and excessive collagen deposition (Laddha and Kulkarni, 2020). This oxidative stress from NOX may also contribute to insulin resistance. Although mitochondria are classically regarded as the major source of free radicals, emerging evidence indicates that NOX significantly contributes to mitochondrial ROS generation in β-cells. This NOX-derived ROS exacerbates β-cell dysfunction by impairing insulin secretion and action, primarily through oxidative damage to cellular components, including DNA, proteins, and lipids (Elumalai et al., 2021).

Beyond the aforementioned ROS-generating pathways, nuclear factor erythroid 2-related factor 2 (Nrf2) serves as a critical regulator of redox homeostasis in both viral hepatitis and diabetes. HCV-mediated suppression of Nrf2-antioxidant response element-regulated genes increases reactive oxygen intermediates, compromising host genome stability and regenerative capacity while promoting HCV pathogenesis (Bender and Hildt, 2019). This process concurrently activates c-Jun N-terminal kinase (JNK), leading to impaired insulin signaling required for hepatic regeneration (Bender and Hildt, 2019). Notably, Nrf2 deficiency in HCV-infected cells downregulates insulin receptor expression, establishing a direct link to insulin resistance (Barthel et al., 2016). HBV similarly modulates Nrf2 activity but through distinct mechanisms. HBV upregulates Nrf2 to enhance insulin receptor biosynthesis while inducing α-taxilin overexpression, which traps insulin receptors intracellularly. This dual effect reduces membrane receptor availability and insulin binding capacity in hepatocytes, as demonstrated in both experimental models and clinical observations (Barthel et al., 2016). Collectively, hepatitis viruses exploit ER stress and oxidative stress pathways to induce insulin resistance and metabolic dysregulation. The NOX-Nrf2 axis emerges as a central coordinator of oxidative damage, inflammatory activation, and insulin signaling impairment, mechanistically connecting viral persistence to diabetes development. These findings reveal novel therapeutic opportunities targeting oxidative stress responses and Nrf2 pathway modulation.

Peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC-1α) functions as a master transcriptional regulator governing mitochondrial biogenesis and functional integrity, including oxidative phosphorylation capacity and ROS detoxification pathways (Rius-Pérez et al., 2020). In viral hepatitis pathogenesis, PGC-1α demonstrates critical regulatory functions. HBV infection triggers silent information regulator 1 (SIRT1) -mediated deacetylation of PGC-1α, which potentiates PPARα transcriptional activity. This molecular cascade ultimately enhances HBV transcriptional activity and viral replication, as validated across experimental models and clinical specimens (Monroy-Ramirez et al., 2021). Yao et al. demonstrated that HCV infection induces ER stress and upregulates both wild-type PGC-1α and its liver-specific PGC-1α. This upregulation enhances HCV replication while concurrently increasing phosphorylated cAMP-response element-binding protein (CREB) levels (Qian et al., 2024). Mechanistically, wild-type PGC-1α expression is regulated by CREB phosphorylation, whereas the liver-specific PGC-1α is modulated through CREB phosphorylation combined with forkhead box O1 (FoxO1) dephosphorylation (Yao et al., 2014). In addition, FOXO1 impedes PGC-1α transcription through its competition with CREB for the binding sites on transcriptional coactivators CREBBP/EP300 (Qian et al., 2024). HCV-mediated upregulation of PGC-1α exhibits tissue-specific metabolic regulatory effects. Current evidence demonstrates that in both human and animal models of T2DM, the expression of PGC-1α and its downstream target genes - which are critically involved in mitochondrial biogenesis and oxidative phosphorylation - is significantly reduced in skeletal muscle and adipose tissue, while being markedly elevated in the liver of diabetic mice (Qian et al., 2024). This tissue-specific expression pattern generates opposing metabolic consequences, with hepatic PGC-1α overexpression increasing glucose output through enhanced gluconeogenesis, whereas skeletal muscle PGC-1α improves glucose utilization by augmenting oxidative capacity (Qian et al., 2024). PGC-1α precisely controls glucose disposal as it’s involved in multiple glucose metabolic processes. For example, it raises muscle glycogen stores by suppressing glycolytic flux and downregulating related enzymes’ expression (Lim et al., 2024). In adipose tissue, diminished PGC-1α levels and impaired insulin signaling molecules correlate with metabolic dysfunction, further aggravating systemic insulin resistance in affected subjects (Qian et al., 2024). Existing evidence demonstrates that hepatitis virus-mediated diabetes progression involves tissue-specific PGC-1α upregulation. For PGC-1α to serve as either a biomarker for diabetes susceptibility or a therapeutic target for glycemic control, precise identification of its tissue-specific actions is essential to mitigate the virus-induced adverse effects on glucose metabolism.

DNA methylation represents a fundamental epigenetic mechanism essential for transcriptional regulation, developmental processes, genomic imprinting, genome stability maintenance, and chromatin organization. This modification is precisely controlled by DNA methyltransferases (DNMTs), methyl-CpG binding domain proteins, and chromatin remodeling factors (Lee et al., 2024). In virally induced malignancies, viral oncoproteins can dysregulate the host methylation machinery through aberrant DNMTs activation, consequently increasing oncogenic risk (Mehdipour et al., 2020). Among DNMT family members, DNMT3A and DNMT3B demonstrate particular pathological significance in hepatitis virus infection. These de novo methyltransferases preferentially target unmethylated DNA substrates, establishing methylation patterns that contribute to viral pathogenesis (Lee et al., 2024). HBx inhibited the expression of protein tyrosine phosphatase non-receptor 13 (PTPN13) by elevating the expression levels of DNMT3A and establishing an interaction with DNMT3A (Dandri, 2020). PTPN13 can significantly inhibit HCC cell proliferation, migration, and invasion, and its overexpression can slow down the progression of HCC cells (Zhan et al., 2016; Dandri, 2020; Yan et al., 2021). Mechanistically, DNMT3A binds to the PTPN13 promoter and induces methylation-mediated silencing. These findings suggest that HBV may promote HCC development via DNA methylation-dependent pathways. The virus-induced elevation of DNMTs levels exhibits dual effects: while hypermethylation of host genes (e.g., PTPN13) disrupts normal cellular functions, methylation of viral DNA may paradoxically suppress HBV replication. Notably, hepatocytes upregulate DNMTs expression as a defensive response against HBV infection (Oropeza et al., 2021). These enzymes can methylate the HBV viral DNA, resulting in reduced viral replication and diminished viral gene expression. However, conflicting evidence exists regarding HBV covalently closed circular DNA (cccDNA) levels during DNMT3A expression. This phenomenon may be linked to the suppression of host factors that normally inhibit cccDNA formation under basal conditions (Brezgin et al., 2019). The upregulation of DNMTs such as DNMT1 and DNMT3b is also linked to HCV core protein (Hassouna et al., 2020), while there is no change in genotypes 2a, 3a, 4h, and 5a except in genotype 1b HCV (Benegiamo et al., 2012).

DNA methylation demonstrates a potential association with diabetes pathogenesis. Comparative analyses reveal elevated DNA methylation levels in the PPAR gamma coactivator 1-alpha (PGC-1α) gene promoter in pancreatic islets from diabetic subjects relative to non-diabetic controls. This epigenetic modification likely suppresses PGC-1α expression, subsequently contributing to hormonal imbalance, dysregulated lipid metabolism, and mitochondrial impairment, ultimately disrupting glucose homeostasis. These findings collectively support a mechanistic link between DNA methylation and diabetes development (Santos et al., 2020). DNA methylation inhibits the expression of the insulin gene, and the promoter of this gene is specifically demethylated in cells responsible for insulin production (Wu et al., 2023), associating variations in DNA methylation with overall body insulin sensitivity. Thus, researchers have already successfully demonstrated the therapeutic role of DNMTs in diabetes. DNMTs inhibitor can improve obesity-induced glucose intolerance and insulin resistance in a manner contingent upon adiponectin (Wang et al., 2023). In addition, someone discovered that deletion of DNMT3A specifically in the adipose tissue of mice protects from DNMT3A-induced insulin resistance (You et al., 2017). Meanwhile, DNMT3A inhibits fibroblast growth factor 21 (Fgf21), an insulin sensitizer (Markan et al., 2014), by elevating the DNA methylation status of the promoter region of Fgf21, which decreases Fgf21 expression, and suppresses its crucial negative regulatory target gene effect in adipocytes (You et al., 2017). Besides, two major epigenetic silencing mechanisms are instrumental in causing the functional immaturity observed in Raptor-deficient β-cells: DNMT3A-dependent DNA methylation and Polycomb repressive complex 2-dependent H3K27me3 modification (Ni et al., 2022). In conclusion, overexpression of DNMTs induced by the hepatitis virus may lead to diabetes susceptibility through epigenetic pathways. Future research can be focused on which genes related to insulin signaling are suppressed by the upregulated DNMTs expression, whether it affects the function of pancreatic β-cells and insulin sensitivity, and the specific impact of DNMTs inhibitors in both diseases.

Histone acetylation, among the earliest identified post-translational modifications of nuclear proteins, serves fundamental structural and functional roles within chromatin. This epigenetic modification dynamically regulates diverse cellular processes spanning transcriptional activation, metabolic programming, proliferation-apoptosis balance, chromatin architecture maintenance, and DNA repair mechanisms (Miziak et al., 2024; Lv et al., 2025b). The counterbalancing deacetylation process, mediated by histone deacetylases (HDACs), equally governs transcriptional regulation. HDAC enzymes catalyze lysine deacetylation on both histone and non-histone substrates, inducing chromatin compaction and subsequent transcriptional silencing of target genes (Lv et al., 2025b). Existing studies have documented reduced expression of both HDAC3 mRNA and protein in HepG2 cells upon HBV infection (Wei and Meng, 2023). Given the established role of histone deacetylation in viral regulation, this observation raises the hypothesis that HBV may exploit HDAC3 downregulation to evade host antiviral defenses, thereby facilitating viral persistence through impaired deacetylation-mediated control of HBV replication. Therefore, research has confirmed that the expression of HDAC3 in HBV-infected mice is relatively weak. Furthermore, evidence suggests that reestablishing this particular signature can inhibit HBV replication, primarily by restricting the transcription of cccDNA (Zhao et al., 2022; Wei and Meng, 2023). Strikingly, IFN-α2b can inhibit this downregulation of HDAC3, controlling the transcription and replication of HBV through facilitating the histone H4K8 de-2-hydroxyisobutyrylation caused by HDAC3 (Zhao et al., 2022). Contrary to HBV, HCV activates HDACs with subsequent acetylation of histones via inducing ROS (Zhou et al., 2018), which means HCV increases the expression of HDACs. The proviral role of HDACs in HCV replication has been experimentally demonstrated. Specifically, treatment with an HDAC3 inhibitor significantly suppressed HCV replication in a murine infection model, providing direct evidence for HDAC3’s involvement in facilitating viral propagation (Zhou et al., 2018). Similarly, the HDAC3 inhibitor RGFP966 has been shown to decrease viral replication in Huh7 cells and in an in vivo model of humanized transgenic mice (Zhou et al., 2018). This is accomplished through the downregulation of Apo-A1 expression, a protein that is essential for maintaining HCV infectivity (Mancone et al., 2011). This process may potentially lead to the suppression of HCV secretion.

Deacetylation exerts dual regulatory effects on glucose homeostasis. First, HDAC-mediated deacetylation can preserve gluconeogenic pathways, as demonstrated by hepatic FOXO1 and FOXO3 serving as specific substrates for HDAC3. Conversely, deacetylation may also suppress glycolytic activity through distinct mechanisms. FOXO1 deacetylation confers protection against oxidative stress-mediated acute β-cell dysfunction, maintaining normal insulin biosynthesis and secretory capacity (Takigawa-Imamura et al., 2003). Beyond regulating FOXO1/3 acetylation status, HDACs additionally suppress TNF-α-driven inflammatory responses. Comparative studies reveal elevated histone H3 acetylation at TNF-α promoter regions in circulating monocytes from diabetic patients versus non-diabetic controls, a modification that enhances inflammatory gene transcription during hyperglycemic episodes (Lu et al., 2021). Conversely, HDAC inhibition demonstrates therapeutic potential for ameliorating insulin resistance. Pharmacological HDAC inhibitors promote glucose transporter type 4 (GLUT4) translocation to the plasma membrane, consequently augmenting both basal and insulin-stimulated glucose uptake in skeletal muscle. These findings underscore the critical regulatory function of HDACs in modulating glucose metabolism, where their activity normally suppresses glucose uptake and contributes to insulin resistance pathogenesis (Takigawa-Imamura et al., 2003). Moreover, previous studies have demonstrated that glucose-stimulated insulin gene expression involves the molecular interplay between pancreatic and duodenal homeobox 1 (PDX-1) and p300 histone acetyltransferase (Mosley and Ozcan, 2003). The p300 protein, possessing intrinsic histone acetyltransferase activity, translocates to the insulin gene promoter through PDX-1 interaction. This recruitment enables local histone acetylation that potently enhances insulin gene transcription and subsequent protein synthesis. Reduced HDACs activity consequently diminishes insulin expression due to impaired deacetylation mechanisms. HDAC3 inhibition exhibits dual protective effects by alleviating T2DM-induced endothelial damage and suppressing β-cell apoptosis. Importantly, HDAC3 blockade significantly attenuates ER stress associated with β-cell dysfunction (He et al., 2023). Additionally, cytokine-mediated pathways combined with impaired NF-κB transactivation collectively exacerbate β-cell apoptosis and functional impairment (Weidemann et al., 2024).

Histone acetyltransferases (HATs) represent the enzymatic counterpart to HDACs in maintaining histone acetylation homeostasis. HAT1-mediated acetylation of nascent histones cooperates with chromatin assembly factors such as chromatin assembly factor-1 (CAF-1) and anti-silencing factor 1 to orchestrate nucleosome deposition. This acetylation-dependent mechanism additionally participates in fundamental nuclear processes spanning DNA replication, transcriptional regulation, damage repair, and chromatin silencing/activation pathways (Hu et al., 2023; Ortega et al., 2024). HATs catalyze lysine residue acetylation on histones, increasing chromatin accessibility for transcription factors, transcriptional machinery, and RNA polymerase II to facilitate gene activation. Emerging evidence indicates that HATs, along with their counterpart HDACs, critically regulate HBV infection. Specifically, the acetylation status of H3/H4 histones bound to cccDNA directly modulates viral replication efficiency (Pollicino et al., 2006). This mechanistic model is supported by elevated expression of HAT1, CAF-1, and hepatocellular carcinoma-associated long non-coding RNA in HBV-infected humanized liver mouse models. Notably, CAF-1 deficiency, specifically its p150 subunit, impairs histone H3/H4 deposition onto HBV cccDNA (Yang et al., 2019). These findings establish that the HAT1/CAF-1 axis mediates HBV cccDNA minichromosome formation through histone H4 lysine 5 and 12 acetylation, while maintaining viral chromatin transcriptional activity (Yang et al., 2019).

Although direct evidence linking HATs to glycemic control remains limited, current studies confirm acetylation’s critical involvement in insulin secretion pathways (Zhang et al., 2019) and gluconeogenic regulation (Mutlu et al., 2024), including insulin signal transduction modulation. Future investigations should prioritize the intersection between viral hepatitis and diabetic acetylation networks, particularly the dual regulatory functions of HDACs and HATs in viral persistence and glucose homeostasis. Therapeutic exploration of HDAC inhibitors for concurrent antiviral and insulin-sensitizing effects may yield novel combination therapies. Given HAT1/CAF-1’s established roles in chromatin biology, further mechanistic studies should evaluate their potential impact on diabetic progression and assess their viability as therapeutic targets.