TIMP1 exerts oncogenic effects in multiple malignant tumors, yet its specific biological functions and molecular mechanisms in glioma remain incompletely elucidated. This study systematically investigated the expression level, clinical prognostic significance and underlying functional mechanisms of TIMP1 in glioma. Pan-cancer analysis verified that TIMP1 is abnormally overexpressed across a wide range of tumor tissues, with particularly prominent upregulation observed in glioma. Its high expression is closely correlated with malignant clinicopathological phenotypes of glioma and serves as an effective indicator of poor overall survival for patients. In vitro functional experiments confirmed that elevated TIMP1 expression accelerates the proliferation, migration and invasion of glioma cells. Mechanistic studies revealed that TIMP1 sustains the malignant progression of glioma by regulating multiple core extracellular matrix genes and activating extracellular matrix signaling pathways. Collectively, TIMP1 facilitates the malignant evolution of glioma via mediating extracellular matrix signaling cascades, and it holds great promise as a novel molecular biomarker for clinical prognostic evaluation and a potential therapeutic target for glioma.
The dysregulated expression of circular RNAs (circRNAs), newly recognized RNA molecules that are widely found across different species, has been implicated in the progression of several cancers, including breast cancer. Our previous research identified a novel circRNA, hsa_circ_0136682, whose expression pattern and potential function in breast cancer remain to be clarified. This study focuses on uncovering the regulatory impact and specific mechanisms of hsa_circ_0136682 in breast cancer progression. Functionally, we observed a significant upregulation of hsa_circ_0136682 in breast cancer cells, which inhibited cell apoptosis. Gain- and loss-of-function experiments confirmed its ability to promote cell proliferation, migration, and invasiveness in breast cancer, both in vitro and in vivo. Mechanistically, our research demonstrated that hsa_circ_0136682 interacts with nucleolin (NCL) to stabilize c-Myc mRNA and enhance protein expression through post-transcriptional regulation. In summary, our findings suggest that hsa_circ_0136682 drives breast cancer progression via the NCL/c-Myc axis. In breast cancer cells，hsa_circ_0136682 interacts with nucleolin (NCL), NCL protein binding to c-Myc mRNA, forming an RNA-protein ternary complex of hsa_circ_0136682/NCL/c-Myc to stabilize c-Myc mRNA and enhance protein expression. Therefore, hsa_circ_0136682 drives breast cancer progression via the NCL/c-Myc axis.
The dysregulation of mRNA modifications, particularly acetylation of cytidine (ac4C), has emerged as a pivotal mechanism in the context of tumor biology, including prostate cancer (PCa), where its exact role mediated by NAT10 remains ill-defined. This study aimed to elucidate the clinical significance of NAT10 in PCa. Our results indicated a pronounced overexpression of NAT10 in PCa tissues and cell lines, which correlated with enhanced cellular proliferation, migration, invasion, and overall tumor growth. Furthermore, acetylated RNA immunoprecipitation sequencing (acRIP-seq) revealed that NAT10 facilitates ac4C modification of MARK2 mRNA, which was consequentially linked to a decrease in mRNA stability and translational efficiency upon NAT10 knockdown, as validated through western blot analysis. Mechanistic investigations demonstrated that NAT10 elevates MARK2 expression, activating the mTOR/HIF-1α/C-Myc signaling cascade, thereby promoting aerobic glycolysis in PCa cells. Consequently, these findings underscore the crucial role of ac4C mRNA modifications in the progression of PCa and position MARK2 as a significant mediator of metabolic reprogramming, suggesting that targeting ac4C mRNA modifications may provide a novel therapeutic strategy for managing prostate cancer.
Vacuolar protein sorting-associated protein 35 (VPS35), a core component of the retromer complex, recognizes cytosolic retrieval signals in cargo proteins and mediates intracellular protein transport. Although previous studies have demonstrated that VPS35 promotes the growth and invasion of gastric cancer (GC), its role and mechanisms in GC chemoresistance remain largely uncharacterized. Here, VPS35 is identified as a potential predictive biomarker for chemotherapy response in GC. Clinically relevant chemotherapeutic agents, including 5-fluorouracil and cisplatin, significantly upregulate VPS35 expression, which is inversely associated with chemosensitivity. Functional assays demonstrate that VPS35 overexpression induces chemoresistance in GC cells, whereas VPS35 knockdown enhances tumor sensitivity to drug-induced cytotoxicity. Mechanistically, VPS35 contributes to chemoresistance by facilitating the nuclear translocation of p65 and activating the NF-κB signaling pathway. These findings suggest that VPS35 may serve as a prognostic biomarker and a promising therapeutic target in GC.
Advanced gene editing tools have transformed oncology by facilitating precise molecular therapies aimed at the hereditary basis of cancer. This thorough study examines the mechanisms, applications, and clinical implementation of advanced genome editing technologies in cancer treatment. This review commences with the molecular principles of genome editing and DNA repair mechanisms, systematically analyzing established technologies such as Zinc Finger Nucleases, Transcription Activator-Like Effector Nucleases, and various CRISPR/Cas systems (Cas9, Cas12, Cas13), in addition to novel advancements including base editors, prime editors, and the PASTE system. Additionally, hybrid platforms such as ARCUS, MegaTALs, and modified recombinases are examined, highlighting their amalgamation with artificial intelligence, biosensors, and synthetic biology concepts. The study outlines significant applications including functional genomics, disease modeling, synthetic lethality screening, and direct therapeutic interventions, with a specific focus on CAR-T cell engineering and immune checkpoint regulation. Applications unique to various cancer types are thoroughly examined throughout lung, breast, colorectal, hematologic, liver, pancreatic, head & neck, esophageal, prostate, gastric, and brain cancers. Significant obstacles such as delivery optimization via viral and non-viral vectors, tumor-specific targeting, off-target effects, immunogenicity, and ethical issues related to germline vs somatic editing are comprehensively examined. The translational landscape is analyzed via current clinical trials, regulatory structures, and the incorporation of organoid models and patient-derived xenografts for the advancement of personalized therapies. This review highlights the transformative impact of gene editing on cancer medicine, advancing toward more accurate, effective, and personalized therapeutic approaches.
Malignant gliomas are common primary brain tumors. Glioblastoma carries a poor prognosis, with median survival of less than 2 years. Given the urgent need for novel therapies, oncolytic virus (OV) therapy has developed rapidly. However, challenges remain with effective OV delivery to tumor sites and efficient infection of tumor cells. This study investigated the use of stem cells from human exfoliated deciduous teeth (SHED) as a potential vehicle for oncolytic herpes simplex virus-1 therapy (SHED-OV) to enhance treatment efficacy. SHED-OV showed a greater reduction in tumor cell viability in vitro than direct OV infection. Migration assays revealed that SHED-OV actively migrated toward glioma cell-conditioned medium, demonstrating their tumor-homing ability. In vivo experiments demonstrated significantly prolonged survival in both the glioma cell/SHED-OV co-implantation group and the OV-infected glioma cell group compared with controls. In a glioma stem cell model, both SHED-OV and OV alone significantly improved survival compared with controls, with SHED-OV achieving anti-tumor effects comparable to those of direct OV administration and complete tumor regression in a subset of mice. SHED-OV also exhibited tumor-homing ability. These results suggest that SHED could serve as an effective vehicle for OV delivery, potentially improving tumor infection and therapeutic efficacy.
Chimeric antigen receptor-engineered NK cells targeting mesothelin (MSLN CAR-NK) have emerged as promising off-the-shelf immunotherapeutics for multiple malignancies. However, their clinical translation remains constrained by inefficient cytotoxic potency and limited persistence. This study investigated the therapeutic potential of nicotinamide mononucleotide (NMN), a metabolic modulator known to enhance immune cell functionality, in augmenting MSLN CAR-NK cell efficacy against ovarian cancer (OC). Through systematic evaluation, we found that NMN supplementation significantly enhanced CAR-NK cell activation marker expression (CD69, NKG2D), degranulation capacity (CD107a+ increased by 21.7 ± 1.1%), and cytokine production (IFN-γ elevated 1.3-fold). In addition, NMN treatment potentiated MSLN CAR-NK cell-mediated cytotoxicity against MSLN+ target cells, achieving 32.8 ± 1.4% specific lysis at an effector-to-target ratio of 25:1, while concurrently reducing cellular apoptosis compared with controls. Mechanistic interrogation via transcriptomic profiling revealed NMN-mediated modulation of PLC-γ phosphorylation cascades and mitochondrial redox homeostasis. Notably, NMN effectively counteracted tumor microenvironment-induced mitochondrial ROS accumulation (reduced by 25.1 ± 0.8% in OC-conditioned medium). Critically, in an OVCAR8-MSLN xenograft model, adoptive transfer of NMN-preconditioned CAR-NK cells led to superior tumor control, reduced proliferation (Ki67), diminished angiogenesis (CD31), and enhanced intratumoral CAR-NK infiltration compared with controls. These findings establish NMN as a clinically relevant adjuvant that augments CAR-NK cell efficacy through dual mechanisms: metabolic enhancement of effector functions and protection against microenvironmental oxidative suppression, thereby offering a translatable strategy to improve CAR-NK therapy for ovarian cancer.
Chemotherapy remains the primary treatment for ovarian cancer (OvCa), and chemoresistance drives patient mortality. Cellular quiescence, reversible exit from the cell cycle, increases chemotherapy resistance as chemotherapies primarily target rapidly proliferating cells. Here, we report that CHD4 and MBD3, components of the nucleosome remodeling and deacetylase (NuRD) complex, are downregulated in quiescent OvCa cells (qOvCa). We find that either CHD4 or MBD3 knockdown or histone deacetylase inhibitors (HDACi), induce quiescence in OvCa cells. RNA-Seq and ATAC-seq analysis of HDACi-treated cells confirmed expression changes consistent with induction of quiescence. Additionally, HDACi-treated cells revealed downregulation of the RHO/RAC pathways. Suggesting downregulation of the RAC pathway could play a role in HDACi-mediated quiescence, RAC inhibitors (RACi) similarly induced quiescence. Both HDACi and RACi resulted in nuclear-to-cytoplasmic shifting of the pro-proliferative transcription factor MRTFA. which has been linked to quiescence. Further analysis of HDACi qOvCa indicated multiple alterations in proteostasis, including increased proteasome activity and autophagy. We find qOvCa cells are dependent on these pathways for survival, such that there is profound synergistic OvCa cell death with HDACi and proteasome- or autophagy-inhibitor combination therapy. Combined, this work supports HDACi as pharmacologic means to induce a quiescent state in OvCa cells and sensitize them to proteostasis-targeting drugs.
Epigenetic regulation governs stem cell fate and perturbations in these mechanisms often lead to tumor development. The CoREST complex, a critical regulator of neural and hematopoietic stem cell differentiation, is recurrently targeted by gain of function mutations in the ubiquitin ligase KBTBD4 in high-risk embryonal brain tumors. However, the tumorigenic potential of these mutations remains unresolved partly due to the challenges in modeling tumors that arise during early brain development. We and others recently demonstrated that small molecule UM171 mimics KBTBD4 mutations by promoting robust CoREST degradation and expansion of hematopoietic stem cells. Leveraging this mechanistic similarity, we modeled KBTBD4 mutations in hematopoietic stem and progenitor cells (HSPCs) and found that mutants induced expansion of immature stem and progenitor populations and impaired lineage differentiation. High-throughput screening identified HDAC inhibitors as specific agents that disrupt mutant KBTBD4 activity, by preventing interaction with the CoREST complex. Using our HSPC model, we demonstrated that the class I HDAC inhibitor mocetinostat alleviated differentiation defects caused by KBTBD4 mutations. Together, these findings reveal the tumorigenic mechanism of KBTBD4 mutations and uncover therapeutic vulnerabilities that may be exploited for clinical applications.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy affecting both children and adults. Given its persistently poor prognosis, there is a critical need to identify additional factors involved in T-ALL oncogenesis and progression. CD9, a membrane protein of the tetraspanin family implicated in diverse cellular processes, has been associated with prognosis in several cancers, yet its role in T-ALL remains poorly understood. In this study, using a mouse model first, we found that CD9 overexpression is associated with leukemic T cells that have migrated outside the thymus into peripheral tissues. Then, analysis of a human T-ALL cohort shows that CD9 expression is heterogeneous, tends to increase at relapse and is enriched in the TAL1⁺ molecular subtype. We further demonstrate that CD9⁺ cells display enhanced migratory capacity compared with CD9⁻ counterparts, and that CD9 levels affect extracellular vesicle biogenesis. Altogether, our findings support a role for CD9 in T-ALL leukemogenesis and highlight its potential involvement in relapse.
Breast cancer (BRCA) development is tightly linked to metabolic dysregulation, with enhanced aerobic glycolysis standing out as a key hallmark, and competing endogenous RNA (ceRNA) mechanisms have emerged as critical epigenetic regulators of tumor metabolic pathways-this study thus aimed to explore glycolytic regulation through ceRNA networks in BRCA, with the goal of identifying potential prognostic biomarkers and mechanistic targets. To achieve this, we integrated comprehensive bioinformatics analyses of The Cancer Genome Atlas (TCGA) dataset with experimental validation to identify PCAT7 as a functionally relevant long non-coding RNA (lncRNA), complemented by functional assays including cell proliferation tests, glucose consumption measurements, and lactate production assays, as well as molecular interaction verification using luciferase reporter assays and RNA immunoprecipitation (RIP). Our results showed that PCAT7 is overexpressed in BRCA tissues and correlates with poor patient prognosis; mechanistically, PCAT7 acts as a molecular sponge for miR-204-5p, alleviating its inhibitory effect on RUNX2 and thereby regulating key glycolytic regulators including GLUT1 and PKM2, while silencing PCAT7 suppresses tumor cell proliferation, invasion, migration, and glycolytic activity in vitro. Collectively, this study uncovers a novel ceRNA network involving PCAT7/miR-204-5p/RUNX2 that drives glycolytic metabolism in BRCA, advancing our understanding of epigenetic regulation in cancer metabolism and highlighting PCAT7 as a potential prognostic biomarker for BRCA patients, with future in vivo studies needed to further validate the therapeutic potential of targeting this axis. Created in https://BioRender.com .
The discovery of potential targets in Head and neck squamous cell carcinomas (HNSCC) through molecular and mechanism analyses is crucial for understanding and treating this disease. This study utilized rigorous methods, including cell lines (FaDu and SCC-15) and a xenograft tumor model. Transfections were conducted using the Lipofectamine 2000 kit, and the evaluation of HOXC11, SPHK1, apoptosis-related protein, and the Wnt signaling pathway was carried out using qPCR and WB methods. The cell proliferation, migration, invasion, and apoptosis were comprehensively evaluated using colony formation, Transwell, wound healing, and flow cytometry, respectively. HOXC11 and SPHK1 are highly expressed in HNSCC and might be involved in the Wnt signaling pathway. HOXC11 promoted cell proliferation, migration, and invasion, inhibiting apoptosis in HNSCC. Silencing SPHK1 inhibited cell progression and dysregulated the Wnt signaling pathway in HNSCC. Overexpressed SPHK1 reversed the functions of sh-HOXC11 in regulating cell progression and the Wnt signaling pathway. HOXC11 promotes HNSCC progression by regulating SPHK1 through the Wnt signaling pathway. Silencing HOXC11 inhibited the tumor growth of HNSCC. Our study demonstrates that HOXC11 promotes HNSCC progression by regulating SPHK1 through the Wnt/β-catenin signaling pathway, identifying a previously unrecognized regulatory axis in HNSCC.
Glypican-3 (GPC3) is an oncofetal cell surface proteoglycan that is highly expressed in hepatocellular carcinoma (HCC) and largely absent from normal adult tissues, making it an attractive target for gene and cell therapies. A broad range of GPC3-directed strategies has been explored, including antibody-based agents, bispecific engagers, chimeric antigen receptor (CAR) and T cell receptor (TCR)-engineered immune cells, vaccine platforms, and emerging radiopharmaceutical approaches. However, durable clinical responses have remained limited. Here, we synthesize biological and translational evidence to examine factors that may constrain the clinical efficacy of GPC3-targeted therapies, including antigen-related features, tumor microenvironment-associated barriers, and platform-specific challenges. Finally, we discuss emerging therapeutic modalities and outline design principles for the rational optimization of next-generation GPC3-directed strategies.
Non-coding RNAs, as microRNAs, long non-coding RNAs, and circular RNAs, are significant modulators of tumor biology and gene expression. miRNAs primarily regulate gene expression at the post-transcriptional level, whereas lncRNAs influence transcriptional activity and epigenetic states. Moreover, circRNAs function as highly stable molecules that shape oncogenic pathways by sequestering miRNAs and interacting with RNA-binding proteins. By addressing these regulatory roles, ncRNAs have emerged as attractive candidates for therapeutic intervention, yet their clinical translation remains limited by rapid degradation, insufficient cellular uptake, and off-target effects. Engineered exosomes—natural nanosized vesicles with strong biocompatibility and barrier-crossing capacity—represent a promising platform to overcome these delivery challenges. This review provides a comprehensive overview of recent advances in exosome engineering for cancer-directed ncRNA delivery. We summarize state-of-the-art strategies designed to enhance loading efficiency, targeting specificity, and therapeutic performance of exosome-mediated delivery systems for miRNAs, lncRNAs, and circRNAs, and outline their growing potential in next-generation cancer therapy.
Small cell lung cancer (SCLC) comprises 15% of lung cancers with a capacity for early and distant metastatic development, high proliferative capacity, and poor survival rates. Ionizing radiation and chemotherapy are effective against early-stage SCLC. This sensitivity wanes over time, however, making treatment difficult. Different types of neoplasms have demonstrated the pivotal role of small extracellular vesicles (sEVs) in disease progression. However, the role of sEVs development in SCLC remains unclear. In this study, the impact of sEVs secretion in SCLC cells was investigated using the CRISPR-Cas9 system to target the RAB27A. The effects of sEVs release inhibition on tumour growth and metastasis were evaluated using micro-PET-CT analysis. A reduction in cellular proliferation as a consequence of sEVs release, along with diminished expression of proteins and RNA (CD9, CD63, and Tsg101) implicated in sEVs secretion in silenced SCLC cells (p < 0.001, p < 0.0001) was detected. The suppression of sEVs release exhibited significant adverse effects on tumor development and metastatic dissemination in the in vivo tumor model. The present study suggests that the targeting of RAB27A could be a viable cancer therapy for SCLC. Targeting the exosomal pathway has the potential to enhance treatment efficacy, and SCLC may depend on sEVs secretion.
Helicobacter pylori (H. pylori) cytotoxin-associated gene A (CagA) critically contributes to gastric cancer (GC) pathogenesis, though its epigenetic control of cancer stemness is incompletely characterized. This study establishes that CagA enhances self-renewal capacity and metastatic potential in GC cells by elevating DNA methyltransferase 1 (DNMT1) expression. Upregulated DNMT1 catalyzes hypermethylation of the brain-expressed X-linked gene 1 (BEX1) promoter, resulting in transcriptional silencing of this tumor suppressor. Functional validation through tumorsphere/colony formation assays and transcriptomic profiling confirmed DNMT1-mediated BEX1 suppression as essential for sustaining stemness phenotypes. Crucially, in vivo models demonstrated that BEX1 overexpression reverses CagA-driven tumor growth and pulmonary metastasis, while BEX1 knockdown compromises the anti-tumor efficacy of DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (DAC). These findings define a novel pathogenic cascade wherein CagA initiates DNMT1-dependent epigenetic silencing of BEX1 to maintain cancer stemness. The mechanistic identification of this CagA-DNMT1-BEX1 axis provides a therapeutic rationale for targeting DNMT1 activity and restoring BEX1 function in metastatic GC. Schematic Illustration of the Molecular Mechanism by Which H. pylori CagA Protein Promotes the Maintenance of Stem Cell-Like Properties in GC Cells via DNMT1-Mediated BEX1 Methylation.
Nephroblastoma, also known as Wilms’ tumor (WT), is the most common malignant renal tumor in children under 5 years of age. Despite a generally favorable prognosis, approximately 15% of cases experience recurrence. Currently, treatment options for refractory and recurrent WT remain limited, and targeted therapeutic strategies are still under investigation. NCBP1 is a core component of the cap-binding complex and plays a role in mRNA processing, transport, and translational regulation; however, its involvement in the initiation and progression of WT has not yet been elucidated. This study utilized bioinformatics analysis to identify that NCBP1 is highly expressed in WT tissues and is associated with a poor prognosis. Molecular experiments further confirmed that NCBP1 is significantly overexpressed in the WT cell lines 17.94 and HFWT. Functional assays demonstrated that silencing NCBP1 suppresses the proliferation, migration, invasion, and tumorigenic potential of both 17.94 and HFWT cells. Through screening for NCBP1-interacting proteins, KPNA2 was identified, and a positive correlation was observed between the expression levels of KPNA2 and NCBP1 in WT tissues. Through RNA immunoprecipitation experiments, we further validated the interaction between NCBP1 and KPNA2 in WT cells. Silencing of NCBP1 resulted in reduced stability and expression levels of KPNA2 mRNA in 17.94 and HFWT cells. Furthermore, KPNA2 overexpression not only enhanced the proliferation, migration, and invasion capabilities of 17.94 and HFWT cells, but also partially counteracted the inhibitory effects of NCBP1 silencing on these malignant cellular behaviors. In conclusion, the findings of this study elucidate the involvement of NCBP1 in the malignant progression of WT. NCBP1 enhances the stability of KPNA2 mRNA, thereby upregulating KPNA2 expression and subsequently promoting the malignant progression of WT cells.
CAR-T cell therapy has shown great success in hematological malignancies. However, this immunotherapeutic strategy faces critical challenges in solid tumors mainly due to the key hurdles brought about by the hostile tumor microenvironment (TME). Effective CAR-T cell therapy in solid tumors is hampered by low tumor infiltration of the administered T cells due to the dense fibrotic nature of the TME and its aberrant vasculature. Also, solid tumors shape a highly immunosuppressive milieu in which the cytotoxic activity and persistence of functional CAR-T cells are abolished. Trefoil factor family (TFF) peptides, especially TFF3, have recently drawn a lot of attention due to their pro-tumor activities. Based on the recent evidence, TFF3 is upregulated in solid tumors where it plays roles in chemotherapy resistance, increased survival, and proliferation of cancer cells, expansion of the immunosuppressive cells and enhanced angiogenesis, which contributes to the aberrant tumor vasculature. In this review, we explore how TFF3 signaling contributes to tumor progression and immune escape, and how its inhibition might reshape the tumor microenvironment (TME) to better support CAR-T cell activity. Mounting evidence suggests that blocking TFF3 could help reduce immunosuppression, restore more normal blood vessel structure, and disrupt the pro-fibrotic and tumor-promoting interactions driven by cancer stem cells (CSCs). At the same time, since TFF3 plays an important role in protecting mucosal tissues and promoting repair after injury, its inhibition needs to be approached carefully. We also discuss strategies to selectively block TFF3 within tumors while minimizing unwanted effects on healthy tissues. Gaining a deeper understanding of how TFF3 contributes to therapy resistance may open up new opportunities to enhance CAR-T cell treatment in solid tumors, either through combination therapies or as a preconditioning step before CAR-T cell infusion.
Retroviral replicating vectors (RRVs) hold promise for cancer gene therapy but face limitations due to their relatively low titers and susceptibility to inactivation by body fluids, limiting their application to intratumoral delivery. To overcome these challenges and target metastatic cancers, we investigated the use of tumor-homing mesenchymal stem cells (MSCs) as RRV carriers in a clinically relevant model of malignant peritoneal mesothelioma. MSCs derived from adipose tissue, bone marrow, and umbilical cord demonstrated significant migration toward mesothelioma cells and were permissive to RRV infection and production. MSCs transferred RRVs to tumor cells more effectively in direct co-culture than in Transwell assays. Using peritoneally disseminated cancer models, we confirmed that MSCs enhanced RRV transfer, even under ascites-mimicking conditions. In vivo biomolecular imaging and flow cytometry revealed markedly reduced RRV transduction under ascites conditions; however, MSC/RRV delivery significantly enhanced intratumoral viral transmission. Furthermore, while both direct RRV and MSC/RRV treatments were effective in non-ascites models, MSC/RRV delivery achieved superior antitumor efficacy in ascites-mimicking models, resulting in robust tumor suppression and prolonged survival. These findings highlight the potential of MSCs to overcome the limitations of RRV and suggest that MSC-based RRV-mediated suicide gene therapy represents a promising strategy for peritoneally disseminated cancers complicated by cancerous ascites.
Chronic hepatitis B virus (HBV) infection is a major etiological factor in the development of hepatocellular carcinoma (HCC), a cancer that causes a large number of cancer-related deaths around the world. Although antiviral treatments are effective, the risk of HCC remains because studies using advanced sequencing have shown that liver cells still carry integrated viral DNA, experience ongoing inflammation, and undergo lasting changes in epigenetic regulation. HBV maintains its genome in liver cells as a chromatin-like cccDNA structure, and with the help of the HBx protein, it manipulates the cell’s chromatin machinery to support viral gene expression and disrupt normal control of enhancers, DNA methylation, and Polycomb regulation. These alterations enhance transcriptional plasticity and, in the context of chronic liver injury and additional somatic mutations, may contribute to malignant transformation. This review highlights recent mechanistic studies that have suggested a pathway linking HBV persistence to chromatin dysfunction. Further, it outlines an emerging therapeutic opportunity with chromatin-directed drugs, as well as rational combinations of these drugs with immunotherapy for HBV-related HCC.
