Search Results (200)

Hepatitis B virus (HBV) infection is a worldwide health concern that infects nearly 254 million people globally and causes more than 1 million deaths annually. The highest prevalence is seen in sub-Saharan Africa and the Western Pacific region. Cirrhosis, liver failure, and hepatocellular carcinoma (HCC) are reported as leading complications of chronic HBV. The route of transmission of this infection is mainly by exposure to infected blood and bodily fluids. Transmission from mother-to-child remains the predominant route in highly endemic areas. Vaccination has significantly reduced HBV seroprevalence and complications. However, incomplete vaccination of newborns continues to be a major obstacle to elimination of the disease. Current prevention strategies include universal vaccination, perinatal prophylaxis with hepatitis B immune globulin, and maternal antiviral therapy in pregnant women with high viral load. The management of chronic hepatitis B virus infection predominantly depends on nucleoside analogs, including entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide, as well as pegylated interferon alfa. These therapies effectively suppress viral replication and reduce the risks of cirrhosis, HCC, and liver-related mortality, but they rarely achieve functional cure characterized by hepatitis B surface antigen loss. The persistence of covalently closed circular DNA (cccDNA) remains a major hindrance in HBV eradication. Therefore, novel therapeutic strategies targeting different stages of the viral life cycle, including capsid assembly modulators, small interfering RNAs, nucleic acid polymers, and cccDNA-directed approaches, are under active investigation. This review summarizes the epidemiology, prevention, current therapies, clinical outcomes, and emerging therapeutic advances in HBV infection, highlighting ongoing efforts toward achieving a functional cure and global HBV elimination. Full article

Background: Mitoxyperilysis is a recently described form of regulated cell death, but its clinical and immunological relevance in hepatocellular carcinoma (HCC) remains unclear. This study investigated the prognostic significance of mitoxyperilysis-related transcriptional activity and its role in remodeling the tumor immune microenvironment. Methods: A Mitoxyperilysis Score was generated by single-sample gene set enrichment analysis. Prognostic associations were evaluated using Kaplan–Meier analysis, multivariable Cox regression, independent cohort validation, and random-effects meta-analysis. Immune infiltration and cell–cell communication were examined using bulk transcriptomic and single-cell RNA-sequencing data. The functional role of ANXA1 was assessed by ELISA, Western blotting, macrophage co-culture, immunofluorescence, flow cytometry, ANXA1 knockdown, and subcutaneous tumor models. Results: High Mitoxyperilysis Scores were associated with shorter overall survival in TCGA-LIHC (log-rank p = 0.032), although the association was attenuated after adjustment for age, sex, stage, grade, and vascular invasion. The adverse survival association was independently reproduced in the Gao2019 CHCC-HBV cohort (log-rank p = 0.00383). Across TCGA-LIHC, GSE14520, and Gao2019 CHCC-HBV, a random-effects analysis showed an overall hazard ratio of 1.42 per 1-standard-deviation increase in score (95% CI, 1.08–1.86; p = 0.011), with substantial between-cohort heterogeneity (I² = 77.5%). High-score tumors displayed increased immune and stromal infiltration, immune-checkpoint expression, and M2-like macrophage enrichment. ANXA1 expression correlated positively with the Mitoxyperilysis Score in independent cohorts. Mitoxyperilysis induction increased both intracellular and extracellular ANXA1, while ANXA1 overexpression promoted CD163⁺CD206⁺ macrophage polarization. ANXA1 knockdown attenuated this response, reduced subcutaneous tumor burden, and decreased intratumoral CD163 staining. Conclusions: Mitoxyperilysis-related transcriptional activity is associated with adverse survival and an M2-enriched immunosuppressive microenvironment in HCC. ANXA1 is an important, although probably not exclusive, mediator of this process and may represent a potential therapeutic target. Full article

Chronic hepatitis B and C are major causes of cirrhosis, hepatocellular carcinoma, and liver-related mortality worldwide. The genetic diversity of hepatitis B virus (HBV) and hepatitis C virus (HCV) influences disease progression, diagnosis, vaccine response, and antiviral treatment. Periods of healthcare disruption, such as the COVID-19 pandemic, reinforce the importance of molecular surveillance to monitor viral genotypes and clinically relevant mutations. This study described the distribution of HBV and HCV genotypes and mutations in Rio de Janeiro, Brazil, during the COVID-19 pandemic. A cross-sectional study included 25 patients (15 HBV and 10 HCV) recruited between 2020 and 2022. Viral nucleic acids were amplified and sequenced by Sanger methodology, and mutations were analyzed using the Geno2pheno platform. HBV genotype A predominated (67%), comprising subgenotypes A1 (40%) and A2 (27%), followed by the rare genotypes B1 (13%), F2 (13%), and G (7%). Among HCV-infected individuals, genotypes 1a (40%) and 1b (30%) predominated, followed by genotypes 4 (20%) and 2 (10%). HBV immune escape mutations (Y100C and T126S) and unusual insertions in the S and RT domains were identified. In HCV, the substitutions C316Y, C316N, and S282R were detected. These findings highlight the importance of molecular surveillance for detecting clinically relevant viral variants. Full article

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection remain leading causes of cirrhosis and hepatocellular carcinoma (HCC) worldwide, and continue to represent a major challenge despite the growing contribution of alcohol-related and metabolic dysfunction-associated steatotic liver disease. Direct-acting antivirals now cure most patients with chronic HCV infection, while nucleos(t)ide analogues durably suppress HBV replication, producing a rapidly expanding population of treated and cured patients. Many nonetheless retain residual fibrosis, portal hypertension and long-term cancer risk, creating a need for non-invasive long-term liver assessment. Multiparametric ultrasound (MPUS) integrates the evaluation of morphology, fibrosis, steatosis, haemodynamics and perfusion within a single examination. This narrative review summarises the evidence supporting MPUS in chronic viral hepatitis, covering elastographic fibrosis assessment, Baveno VII liver and spleen stiffness criteria for clinically significant portal hypertension, contrast-enhanced ultrasound characterisation of focal liver lesions, and emerging techniques such as microvascular and viscosity-sensitive imaging. Particular attention is given to the confounding effect of inflammatory activity on liver stiffness. MPUS is presented here as a proposed evaluation framework for organising complementary measurements within a single examination, and not as an approach of demonstrated clinical superiority: no comparative or outcome-based study has yet shown that acquiring these parameters together improves clinical decisions relative to the individual techniques applied according to current guidelines. Within this framework, the most plausible role of MPUS in the elimination era is longitudinal assessment of the treated liver, a proposition that requires prospective validation against clinical endpoints. Full article

Aflatoxin B₁ (AFB₁), a dietary mycotoxin classified as a Group 1 carcinogen and a risk factor for hepatocellular carcinoma (HCC), has seen limited biomarker-based evidence linking it to HCC in South America despite favorable regional contamination conditions. Utilizing a newly validated isotope-dilution HPLC–MS/MS method to quantify AFB₁-Lysine (AFB₁-Lys) adducts, we conducted a cross-sectional study involving 92 HCC patients and 70 healthy controls across six South American nations. The primary case–control analysis, focusing on 64 HCC patients and 70 controls from Argentina and Colombia, revealed that AFB₁-Lys concentrations and positivity rates were significantly higher in HCC cases compared to controls (7.16 vs. 0.89 pg/mg albumin; 43% vs. 10%). Multivariable logistic regression demonstrated that detectable AFB₁-Lys was significantly and independently associated with HCC (adjusted OR = 3.72), with associations most pronounced, though based on small subgroups, in viral hepatitis-related and cryptogenic HCC. Furthermore, broader regional analysis indicated higher AFB₁-Lys positivity rates in HBV-positive patients than in HCV-positive or non-viral HCC cases. Ultimately, chronic dietary aflatoxin exposure shows a consistent, statistically significant association with hepatocarcinogenesis across diverse etiological backgrounds in South America, highlighting an urgent need for integrated regional food safety surveillance and expanded prospective studies. Full article

Background and Objectives: In Taiwan, hepatitis B virus (HBV) or hepatitis C virus (HCV) infections are the most common causes of hepatocellular carcinoma (HCC). However, an increasing number of non-HBV and non-HCV (NBNC) patients developing HCC has been noted in recent years. The pathogenic connection between NBNC status and HCC development remains largely elusive. This study aims to explore the differences in clinical manifestations and pathological findings among HCC patients with HBV, HCV, and NBNC etiologies. Methods: This retrospective study analyzed 521 HCC patients with complete hepatic viral profiles at a single medical center in Taiwan between 2016 and 2020. Differentially expressed gene (DEG) analysis, xCell stromal cell estimation, and Gene Set Enrichment Analysis (GSEA) were employed to explore the distinct oncogenic mechanisms between the viral and NBNC groups. Results: The final cohort included 38 NBNC-HCC patients. Clinically, the NBNC-HCC patients exhibited a significantly lower FIB-4 index than the HCV-HCC patients (3.191 vs. 6.077, p = 0.0019). Furthermore, fewer NBNC-HCC patients presented with imaging-defined cirrhosis compared to HBV-HCC patients (44.4% vs. 68.1%, p = 0.0057), and a lower proportion had high Ishak scores (5–6) compared to HCV-HCC patients (31.3% vs. 75.6%, p = 0.0025). DEG analysis revealed differential expression in oncogenes (OIT3, AKR1B10) and liver fibrosis-related genes (COLEC10, CXCL14, and LINC01093). Subsequent GSEA and stromal cell analyses highlighted significant differential enrichment in hepatic stellate cells and vascular endothelial cells. Conclusions: NBNC-HCC patients present with significantly lower rates of cirrhosis and fibrosis compared to their viral counterparts. The distinct gene expression profiles and cell-type enrichment features observed between the viral and NBNC groups indicate a divergent, etiology-specific pathogenesis driving NBNC-HCC. Full article

Oncogenic viruses contribute to approximately 20% of human cancers globally, with their impact falling disproportionately on populations in Sub-Saharan Africa. In this region, cervical cancer, hepatocellular carcinoma, endemic Burkitt lymphoma, and Kaposi sarcoma represent major causes of cancer-related morbidity and mortality, driven by persistent infection with human papillomavirus (HPV), hepatitis B and C viruses (HBV/HCV), Epstein–Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV), and human T-lymphotropic virus-1 (HTLV-1). This review synthesizes current insights into the immunological mechanisms that underpin viral carcinogenesis in Africa, emphasizing how defective viral clearance, chronic immune activation, and immune evasion arise from the convergence of region-specific co-infections, host genetic diversity, and environmental exposures. We examine the mechanistic roles of HIV-associated CD4⁺ T cell depletion, malaria-induced perturbation of antiviral T cell immunity, helminth-driven T helper 2 polarization, and tuberculosis-associated inflammatory signaling in promoting viral persistence and malignant transformation. In addition, the influence of the extensive diversity of African human leukocyte antigens (HLA) and cytokine gene polymorphisms on antiviral immune responses and cancer susceptibility was discussed. We also assessed how virus-associated tumors establish profoundly immunosuppressive microenvironments characterized by impaired antigen presentation and the dominance of immune checkpoint pathways. Finally, we examined how gaps in vaccination, screening, and diagnostic capacity intersect with immunological vulnerability across Africa, contributing to the burden of infection-associated cancers. These challenges position Africa as a critical setting for developing targeted, genotype-inclusive public health interventions and reducing global cancer disparities through advances in immunoprevention and immunotherapy. Full article

Background/Objectives: Hepatitis B virus (HBV) infection remains a major global health challenge because of its association with cirrhosis, hepatic failure, and hepatocellular carcinoma. Patients receiving rituximab-containing regimens are at particularly high risk for HBV reactivation due to profound B-cell depletion and prolonged immunosuppression. This study aimed to evaluate HBV serologic testing practices before rituximab initiation and to assess the incidence and outcomes of HBV reactivation among patients treated with rituximab at a tertiary care center in Jeddah, Saudi Arabia. Methods: A retrospective observational study was conducted on patients who received rituximab between 2010 and 2020 at a tertiary university hospital in Jeddah, Saudi Arabia. Demographic, clinical, laboratory, and treatment-related data were collected from electronic medical records. HBV reactivation was defined according to the American Association for the Study of Liver Diseases (AASLD) criteria. Results: A total of 611 patients were included. HBV serologic testing prior to rituximab initiation was documented in 60.8% of patients with hematological malignancies and 71.7% of those with non-hematological diseases. HBV reactivation occurred in 7 patients (3.4%) in the hematological malignancy cohort, all with lymphoma. Nine patients received antiviral prophylaxis. HBV reactivation was associated with significant morbidity, and liver-related mortality occurred in 28% of reactivation cases. Conclusions: HBV serologic testing was not universally documented prior to rituximab initiation, and antiviral prophylaxis was received by few patients. HBV reactivation was associated with significant morbidity and mortality. These findings support the need for systematic HBV evaluation and prophylaxis protocols in patients receiving rituximab. Full article

Purpose: Nucleotide metabolism plays a critical role in cancer development, but the prognostic significance of genetic variants in nucleotide metabolism genes for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients remains unclear. Methods: We performed Cox proportional hazards regression analyses to evaluate the association between genetic variants in 94 nucleotide metabolism-related genes and overall survival (OS) in 866 HBV-HCC patients. To assess the potential biological relevance of the identified variants, the Bayesian false discovery probability and false-positive report probability were applied for multiple testing correction. Results: Two independent SNPs, DCTD rs17074255 G>A (HR = 1.22, 95% CI: 1.06–1.40, p = 0.005) and ENTPD2 rs3763662 G>A (HR = 1.18, 95% CI: 1.03–1.34, p = 0.015), were significantly associated with OS. A significant dose-dependent association between the number of risk genotypes and poorer OS was observed (P_trend < 0.001). Luciferase reporter assays demonstrated allele-specific regulatory effects of rs3763662 on ENTPD2 expression (p < 0.001). DCTD and ENTPD2 mRNA expression levels were significantly elevated in HCC tumors in the UALCAN database and in our 103 paired samples. Higher expression levels of both genes were associated with poorer survival in the TCGA cohort (p = 0.003 and p < 0.001). Conclusions: Our findings suggest that ENTPD2 rs3763662 (supported by direct functional evidence) and DCTD rs17074255 (supported by eQTL and expression associations) may serve as potential prognostic indicators for HBV-HCC through the regulation of mRNA expression. These findings provide new insights into the role of nucleotide metabolism-related genetic variation in HBV-HCC progression and may facilitate prognostic assessment, pending replication in independent cohorts. Full article

Objectives: The histologic grade is an important prognostic factor in hepatocellular carcinoma (HCC). A Gd-EOB-DTPA-enhanced MRI may provide noninvasive imaging markers related to tumour differentiation. This study aimed to evaluate the association of Gd-EOB-DTPA-enhanced MRI features, together with the albumin–bilirubin (ALBI) score and alpha-fetoprotein (AFP), with the HCC histologic grade and to assess the performance of combined predictive models. Methods: In this prospective cross-sectional study, 75 patients (mean age, 56.4 years; 66 men) with 88 histopathologically confirmed HCC lesions were enrolled. Patients were classified into well-differentiated (grades I–II, n = 24) and poorly differentiated (grades III–IV, n = 51) groups according to the Edmondson–Steiner system. The MRIs were performed on a 1.5-T scanner and included T1-weighted in-phase/opposed-phase imaging; T2-weighted imaging; diffusion-weighted imaging; and dynamic Gd-EOB-DTPA-enhanced sequences, including arterial, portal venous, transitional, and 20 min hepatobiliary phases. Two radiologists, blinded to the pathology, assessed predefined imaging features, and the lesion-to-liver ratio (LLR) was measured. Group comparisons were performed using Student’s t-test, a Mann–Whitney U test, and a chi-square or Fisher’s exact test, followed by a multivariable logistic regression and ROC analysis with bootstrap resampling. Results: Compared with well-differentiated HCC, poorly differentiated HCC showed a higher frequency of peritumoral hepatobiliary phase (HBP) hypointensity (62.7% vs. 4.2%, p < 0.001) and peritumoral arterial hyperintensity (39.2% vs. 0%, p < 0.001). In the multivariable analysis, peritumoral HBP hypointensity remained independently associated with poorly differentiated HCC (OR = 30.89, p = 0.002). The two-parameter MRI model, including peritumoral HBP hypointensity and HBP tumour signal, yielded an AUC of 0.84. The combined MRI + ALBI + AFP model yielded an AUC of 0.87 and an accuracy of 78.7%, representing only a small exploratory improvement over the two-parameter MRI model (AUC = 0.84) in this cohort. Conclusions: Gd-EOB-DTPA-enhanced MRI features, particularly peritumoral HBP hypointensity, were associated with a high histologic grade in HCC. In this surgically treated, predominantly HBV-related cohort with mostly preserved liver function, these findings provide a preliminary basis for preoperative histologic risk stratification; however, they remain exploratory and require external validation in larger, more diverse cohorts before broader clinical application. Full article

Chronic hepatitis B virus (HBV) infection remains one of the main causes of hepatocellular carcinoma (HCC), even though vaccination and long-term viral suppression have reduced new infections and circulating viral replication. This residual cancer risk suggests that serum HBV DNA alone does not capture the full biology of HBV-related carcinogenesis. Hepatitis B virus X protein (HBx) is a relevant entry point because it maintains the transcriptional competence of covalently closed circular DNA (cccDNA), engages host chromatin regulators, and may persist in tumors as cccDNA-derived, integration-derived, full-length, truncated, or fusion forms. This review focuses on a specific question: does the available literature support HBx-associated reactivation of the IGF2 locus in chronic HBV infection and HBV-related hepatocarcinogenesis, and, if so, at which regulatory layer is the claim defensible? The most direct evidence remains promoter-proximal. Classic mechanistic work shows acute HBx-dependent activation of IGF2 promoter P4 through Sp1- and PKC/ERK-dependent signaling. Human tissue and cell-based studies also support a broader fetal-promoter compartment, including P3/P4 transcript enrichment, local promoter hypomethylation, MBD2-HBx-CBP/p300 recruitment, and increased histone H3/H4 acetylation. These observations do not, however, establish HBV exclusivity, uniform loss of imprinting, or direct HBx-mediated rewiring of the human IGF2/H19 topological domain. Recent integration-aware and long-read studies further argue against treating tumor-stage HBx as a single biological variable. In the present evidence framework, HBx-associated IGF2 locus reactivation is therefore more appropriately viewed as a stage-aware, promoter-resolved, biomarker-oriented hypothesis than as a universal mechanism or a treatment algorithm for HBV-related HCC. Full article

There have been reports of an association between the gut microbiota and the development of chronic liver disease, fibrosis, and carcinogenesis; however, it is not yet possible to reach a definite conclusion. In this cross-sectional study, we examined the association between the presence or absence of hepatocellular carcinoma (HCC) and the gut microbiota in patients with chronic hepatitis B virus (HBV) infection. The study subjects consisted of 62 consecutive HBV patients admitted to our hospital who provided informed consent to participate in the study. We performed 16S rRNA analysis using DNA extracted from fecal pellets. The sequencing depth per sample was 80,000 to 90,000 reads. We calculated the proportion of each bacterial genus so that the total for each sample added up to 100%. The male-to-female ratio was 49/13, the median age was 67 years, and 46 of the patients had HCC. Twenty microbial phyla spanning 41 classes, 79 orders, 163 families, and 431 genera were identified. Receiver operating characteristic (ROC) analysis was performed on the identified bacterial taxa, from the level of phylum down to genus, to assess their ability to distinguish between patients with and without HCC. Several bacteria with an area under the curve (AUC) > 0.65 were identified as follows: TM7 phylum TM7-3 class (AUC = 0.700); Firmicutes phylum Clostridiales class Lachnobacterium genus, Dialister genus, Ruminococcus genus, and Roseburia genus (AUC = 0.670, 0.668, 0.667, and 0.660, respectively); and Firmicutes phylum Erysipelotrichi class (AUC = 0.656). Combining three of these taxa resulted in high discriminative power (p = 0.000585) with a sensitivity and specificity of 0.761 and 0.750, respectively. A similar trend was observed in the subgroup analysis based on liver reserve capacity. Even after adjusting for factors related to liver reserve capacity in the multivariate analysis, an association between these bacterial genera and HCC was confirmed. Our results suggest that gut microbiota may be associated with the prevalence of HCC in HBV patients. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, increasingly driven by metabolic dysfunction-associated steatotic liver disease alongside viral and alcohol-related cirrhosis. The tolerogenic immune environment of the liver enables tumor immune escape, with regulatory T cells (Tregs) playing a central role. This review synthesizes human-focused evidence (tissues, blood, clinical cohorts, and single-cell/spatial studies) through September 2025 to define how Tregs are recruited, maintained, and functionally deployed in HCC. Across datasets, intratumoral effector-like Tregs (eTregs) expressing ICOS, CTLA-4, CCR8, and CD39/CD73 accumulate within tumors and co-localize with exhausted cytotoxic PD-1^hi CD8⁺ T cells and suppressive myeloid cells. Recruitment is driven mainly by CCL20–CCR6 and CCL22/CCL17–CCR4 signaling, while CCR8 marks highly suppressive tumor-resident Tregs. Their persistence is supported by TGF-β, IL-10, IL-35, adenosine signaling, IL-2 sequestration, and metabolic adaptation. Spatial biomarkers, including ICOS⁺/CCR8⁺ eTreg density and CD8:Treg ratios, associate with prognosis and emerging immunotherapy responses. Etiology further shapes immune architecture: HBV-related HCC often forms Treg-exhausted T-cell niches around viral antigens, whereas MASLD/MASH promotes stromal and metabolic barriers that may reduce PD-(L)1 efficacy. Current treatments (PD-(L)1 blockade with anti-VEGF or CTLA-4, and some TKIs) intersect with Treg biology, while emerging strategies targeting CCR8, CCR4, ICOS, or the adenosine pathway aim to selectively disrupt intratumoral eTreg networks. This review underscores that an etiology-aware, spatial-biomarker framework may guide the integration of selective Treg targeting with PD-(L)1-based therapies in HCC. Full article

Background: Southeast Asian Americans (SEAAs) experience a disproportionately high burden of hepatocellular carcinoma (HCC), with incidence in several subgroups (i.e., Cambodian, Laotian, and Vietnamese individuals) reaching up to nine times that of non-Hispanic Whites. HCC in SEAAs is largely driven by chronic hepatitis B (HBV), hepatitis C (HCV), metabolic dysfunction–associated steatotic liver disease (MASLD), and alcohol-associated liver disease (ALD). Despite established screening guidelines, under-detection and delayed diagnosis remain common. Objective: To summarize epidemiologic patterns, risk factors, screening challenges, and potential interventions aimed at reducing HCC disparities among SEAAs. Design and Methods: This narrative review synthesized evidence from population based epidemiologic studies, community-based interventions, health services research, and policy analyses. Attention was given to studies reporting disaggregated SEAA subgroup data. Findings derived from SEAA specific studies were distinguished from evidence drawn from broader Asian American or general cirrhosis populations, with inferential steps explicitly noted where subgroup specific data were limited. Key Findings: HCC incidence varies widely across SEAA subgroups, with elevated HBV- and HCV-related HCC in Vietnamese, Cambodian, and Laotian communities, and increasing MASLD-related HCC including among lean individuals who fall outside many surveillance frameworks. Screening and surveillance remain suboptimal, with fewer than 30% of patients with cirrhosis receiving recommended semiannual HCC surveillance and even lower uptake among SEAAs. Barriers include low HBV/HCV screening rates, limited disease awareness, language barriers, underinsurance, provider knowledge gaps, and lack of automated EHR-based reminders. Structural challenges such as poverty, transportation barriers, and limited access to specialty care further delay diagnosis. Proposed Interventions: Culturally tailored outreach programs, bilingual navigators, and community-based screening initiatives have demonstrated improved HBV/HCV testing and linkage to care. AI-enabled EHR tools may enhance identification of high-risk patients, streamline follow-up, and increase surveillance adherence. Expanded use of non-invasive fibrosis assessment and recognition of MASLD-related risk in non-obese individuals may support earlier detection. Policy priorities include mandatory Asian subgroup data disaggregation, expanded insurance coverage, and strengthened community-level healthcare infrastructure. Conclusions: SEAAs face a substantial and preventable HCC burden. A coordinated approach combining culturally tailored community engagement, improved provider support systems, and policy reforms is essential to improving early detection and reducing HCC disparities in this diverse population. Full article

Background: Tumor-associated macrophages (TAMs) are key components of the hepatocellular carcinoma (HCC) microenvironment, but their spatial heterogeneity remains incompletely characterized. We aimed to assess the biological and prognostic relevance of a BAG3-associated TAM program in HCC. Methods: Public single-cell RNA sequencing (scRNA-seq) datasets were analyzed to characterize TAM heterogeneity, and an integrated validation scRNA-seq dataset was used to assess reproducibility. Spatial transcriptomics was used to provide spatial context in a small treatment-exposed cohort. Pseudotime, regulatory network, and cell–cell communication analyses were performed to characterize state transitions and microenvironmental interactions. Survival modeling evaluated the prognostic relevance of the BAG3-associated program. Results: Five TAM subsets were identified, including MARCO⁺, MT⁺ RTM−, MMP9⁺, UBE2C⁺, and BAG3⁺ TAMs. Among them, BAG3⁺ TAMs, a less well-characterized subset, exhibited coordinated stress-adaptive, proteostasis-related, and matrix-remodeling programs that were reproduced in the validation dataset. Pseudotime analysis suggested a continuum of TAM states, with BAG3⁺ TAM stress-remodeling features enriched toward late pseudotime. Communication analysis centered on BAG3⁺ TAMs suggested crosstalk between inflammatory stress cues and angiogenic, stromal-remodeling, and immunomodulatory programs; this pattern was primarily supported by HBV-derived samples and recurrently involved the MIF–CD74 axis. Spatial mapping further supported BAG3⁺ TAM-enriched niches with elevated AP-1, EGR1, and NFKB1 activity. A BAG3-associated risk score derived from a 10-gene signature remained an independent prognostic factor for overall survival after clinical adjustment. Conclusions: These findings characterize a BAG3-associated TAM program with spatial, immunoregulatory, and prognostic relevance in HCC, and support its further evaluation in biomarker and mechanistic studies. Full article