Search Results (6,277)

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, affecting approximately 50 million people worldwide. An estimated 15–30% of individuals with chronic HCV infection progress to cirrhosis, which may subsequently develop into hepatocellular carcinoma. Beyond liver disease, HCV is associated with a broad spectrum of extrahepatic manifestations, particularly mixed cryoglobulinemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL). Persistent viral infection induces chronic antigenic stimulation of B lymphocytes, a key pathogenic mechanism underlying the progression from MC to overt B-NHL. These observations have important therapeutic implications and support the use of antiviral therapy as a cornerstone of treatment. The efficacy of direct-acting antivirals (DAAs) has been well established in patients with HCV-related MC and cryoglobulinemic vasculitis. Several studies have shown that DAAs achieve sustained virologic response rates exceeding 90%, often approaching 100% in contemporary cohorts. Viral eradication is frequently associated with clinical and immunological improvement, as well as regression of cryoglobulinemia. Encouraging outcomes have also been reported in patients with HCV-associated indolent B-NHL, particularly marginal zone lymphoma, although confirmation in larger studies with longer follow-up is needed. In patients with HCV-positive aggressive lymphomas, DAAs have been safely administered in combination with immunochemotherapy, yielding promising results. This review summarizes the current evidence on HCV-associated MC and B-NHL and discusses the impact of DAA therapy on the clinical course and management of these disorders. Full article

Background: Neutrophil extracellular traps (NETs) promote tumor progression and immune evasion across multiple cancers. However, the mechanisms governing NET formation (NETosis) within the tumor immune microenvironment remain incompletely understood. Low P2RY13 expression is associated with the pro-tumor activity of neutrophils in lung adenocarcinoma. Methods: Pan-cancer bioinformatics analyses were performed, including differential gene expression, prognostic, tumor-infiltrating immune cell, and NET scoring analyses. Single-cell profiling was conducted using the Tumor Immune Single-cell Hub 2 database. Immunohistochemical (IHC) and multiplex immunofluorescence (mIF) staining of tissue microarrays (TMAs) was performed to validate findings in lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), and colorectal cancer (CRC). In vitro validation was conducted using gene modulation, tumor-cell-conditioned medium (CM) education, tumor-associated macrophage (TAM)-like macrophage CM transfer, immunofluorescence staining, and ELISA. Results: Bioinformatics analyses suggested that P2RY13 is frequently dysregulated in multiple cancers and that low P2RY13 expression is associated with poor prognosis and reduced immunotherapy responsiveness. Single-cell analyses revealed that P2RY13 is predominantly expressed in TAMs rather than tumor cells. Macrophages without detectable P2RY13 transcripts were markedly enriched in tumor tissues compared with paired normal tissues, and their high infiltration appeared to be associated with elevated NET scores. Tissue microarray-based IHC and mIF analyses further validated this infiltration pattern in LUAD, LIHC, and CRC. In vitro, CM from P2RY13-silenced, tumor-educated TAM-like macrophages enhanced neutrophil NETosis, whereas P2RY13 re-expression attenuated this effect. Furthermore, TMA staining indicated a positive correlation between P2RY13⁻CD68⁺ TAM infiltration and NET expression in the three malignancies. Conclusions: We identified a potentially conserved NETosis-regulating pattern in multiple cancers in which P2RY13-negative TAMs promote NET formation and are associated with adverse clinical outcomes. These findings suggest a previously unrecognized tumor-promoting mechanism and highlight potential therapeutic targets for cancer treatment. Full article

Photothermally induced hyperthermia with safe, localized, and effective optical power densities is critically important to patients’ comfort level and safety in cancer therapeutic applications. This research study explores cesium tungsten oxide (CsWO₃) NPs as the kernel of a drug-release nanocomposite that releases a cancer drug upon near-infrared irradiation. The nanocomposite was functionalized with thermo-sensitive hydrogels to upload Doxorubicin and Cisplatin, characterized and assessed for its therapeutic efficacies against the cancerous gastric cells and hepatocytes. The nanocomposites reached 40.5 °C in 15 min when irradiated at 500 mW/cm² and respectively yielded 37% and 41% of release rates for Doxorubicin and Cisplatin over a span of 24 h. The analysis indicates that the nanocomposites effectively reduced the survival rates of the hepatocellular carcinoma cells and the cancerous gastric cells by 24.2% and 23.9% at 400~500 mW/cm² while minimizing the damaging effects on the healthy cells by 24.3% when compared to those of pure substances. This work highlights the great potential of CsWO₃ NP for constructing drug-release platforms with minimal optical power density and safe NP concentration. Full article

Hepatocellular carcinoma (HCC) is one of the most frequent and lethal malignancies worldwide, with substantial molecular and clinical heterogeneity that complicates prognostic assessment. We aimed to identify molecular subgroups with distinct prognostic profiles using a graph-based multi-omics approach. Similarity Network Fusion (SNF) was applied to integrate mRNA and miRNA sequencing data from the TCGA-LIHC cohort (366 patients), and spectral clustering on the fused similarity network was used to identify patient subgroups. Survival differences were assessed by log-rank test and Cox regression; subgroup characterisation combined direction-aware over-representation analysis and one-versus-all differential expression. Six clusters with distinct survival trajectories were identified in the discovery cohort (exploratory log-rank p-value = 3.6 × 10⁻⁴). C1 (24.3% of patients) showed the worst prognosis (median OS 22.6 months; 5-year OS 28.0%), while C4 reached the best outcomes (median OS not reached; HR 0.34, p-value = 0.001). Cluster membership retained independent prognostic value after adjustment for age, sex and AJCC stage. Each cluster was assigned a descriptive transcriptional label (proliferative–oncofoetal, xenobiotic-metabolising, imprinted/fetal-reactivated, hepatocyte-zonation-like, cholangio-mesenchymal, mature-hepatocyte). As independent evidence of prognostic relevance, the subtype structure was reproduced in a differently profiled external cohort (GSE14520; log-rank p-value = 0.011), with the poor-prognosis (C1) and favourable (C4) subtypes retaining their ordering. SNF-based integration provides a reproducible framework for prognostically informative patient stratification in HCC, with the molecular descriptors serving as starting points for downstream biological characterisation on independent cohorts. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of liver injury ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), a progressive inflammatory state associated with hepatocyte injury, fibrosis, cirrhosis, and hepatocellular carcinoma. Increasing evidence suggests that progression to MASH is not spatially uniform across the liver. Instead, it reflects region-specific metabolic stress, inflammatory signaling, and fibrogenic remodeling along the porto-central axis of the hepatic lobule. Recent advances in spatial transcriptomics, lipidomics, proteomics, and multiplex imaging have provided new insight into how hepatocytes, immune cells, endothelial cells, and hepatic stellate cells interact within distinct hepatic microenvironments during disease progression. In this review, we discuss emerging concepts linking hepatic zonation to steatosis, inflammation, fibrosis, and extracellular matrix remodeling in MASLD and MASH. We highlight how disruption of normal lobular organization contributes to a progressive loss of metabolic compartmentalization and to the amplification of inflammatory and fibrogenic signaling. We additionally examine how spatial disease programs differ between adult and pediatric MASLD, particularly given the periportal-predominant injury patterns frequently observed in children and the current lack of pediatric-focused mechanistic studies. Finally, we discuss recently approved therapies and emerging therapeutic strategies within the context of hepatic microenvironment remodeling and disease heterogeneity. Collectively, these findings support a framework in which MASLD and MASH are spatially organized diseases driven by dynamic multicellular interactions, emphasizing the importance of incorporating zonation and tissue context into future mechanistic studies and therapeutic development. Full article

Objective: Vasculogenic mimicry (VM), characterized by the de novo formation of microvascular-like channels derived from aggressive tumor cells without involving traditional endothelial cells, is a pivotal pathological hallmark driving extreme invasiveness and dismal prognosis in hepatocellular carcinoma (HCC). This study aimed to establish a VM-based molecular subtyping system and systematically characterize its associated biological features, thereby providing a potential framework for individualized prognostic assessment and treatment decision-making in HCC. Methods: We integrated curated VM-associated gene sets with single-cell RNA sequencing data to identify malignant epithelial cell-enriched VM-associated candidate genes. Subsequently, univariate Cox regression, LASSO-Cox regression, and multivariate Cox regression were sequentially performed to identify six prognostic VM-related genes: HSPA9, TGFA, MAD2L1, PROM1, AGXT, and GCGR. HCC patients were stratified into VM, Mixed-VM, and Non-VM subtypes according to VM scores. Kaplan–Meier survival analysis, time-dependent ROC analysis, and Cox regression were used to assess prognostic performance. The biological features of the classification system were evaluated using bulk transcriptomic cohorts, spatial transcriptomics, Cytometry by Time-of-Flight (CyTOF), metabolomics, lipidomics, somatic mutation and copy number alteration analyses, and treatment-related HCC cohorts. Results: The VM score-based classification stratified HCC patients into three molecular subtypes with distinct prognostic and biological characteristics. Patients classified as the VM subtype had significantly poorer overall survival than those classified as Mixed-VM or Non-VM subtypes, and this prognostic pattern was validated across independent cohorts. Multi-omics analyses showed that the VM subtype was associated with YAP-TAZ-TEAD-related transcriptional programs, stemness/proliferation-related features, immunoregulatory and exhaustion-like tumor microenvironmental characteristics, and distinct metabolic and lipidomic alterations involving modified nucleosides, keto acid-related metabolites, cholesteryl esters, and sphingolipid-related species. Spatial transcriptomics revealed focal enrichment of VM-score-high regions and their association with YAP-TAZ-TEAD and immune checkpoint-related signatures. In orthotopic HCC mouse models, YAP1 overexpression increased PAS⁺/CD34⁻ VM-like structures, whereas verteporfin treatment reduced these structures. In two treatment-related cohorts, the Non-VM subtype showed higher response rates to sorafenib and transarterial chemoembolization (TACE) than the VM subtype. Connectivity Map (CMap)-based computational drug prioritization and molecular docking analysis prioritized ivermectin as a candidate compound; however, its antitumor activity requires further experimental validation. Conclusions: This study establishes a VM score-based molecular classification framework for HCC and identifies VM-subtype-associated prognostic, spatial, immune, metabolic, genomic, and therapeutic features. These findings provide a candidate framework for molecular risk stratification and subtype-guided therapeutic exploration in HCC. Full article

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Although the STRIDE regimen (durvalumab plus tremelimumab) has demonstrated an overall survival benefit in clinical trials, real-world evidence remains limited, particularly in Turkish clinical practice. This study aimed to evaluate the effectiveness and safety of first-line STRIDE therapy in patients with unresectable HCC treated in routine clinical practice. Methods: We conducted a retrospective multicenter study including patients with unresectable HCC who received first-line durvalumab plus tremelimumab through the Turkish national Early Access Program across 18 oncology centers. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method, and exploratory Cox regression analyses were performed to evaluate baseline prognostic factors. Results: Thirty-two patients were included. The median PFS was 7.25 months (95% CI, 3.68–22.29), and the median OS was 11.43 months (95% CI, 4.50–not reached). The underlying liver disease etiology was non-viral in 53.1% of patients, hepatitis B virus in 40.6%, and hepatitis C virus in 6.3%. Grade ≥ 3 treatment-related adverse events occurred in fewer than 10% of patients. Conclusions: In this multicenter real-world cohort, first-line durvalumab plus tremelimumab appeared to be a feasible treatment option and was generally well tolerated in patients with unresectable HCC. However, given the retrospective design, small sample size, and absence of a control group, these findings should be interpreted cautiously and require confirmation in larger prospective comparative studies. Full article

Inadequate supply of oxygen causing hypoxic cellular stress drives metabolic reprograming across diverse physiological conditions, including cancer. The activation of hypoxia-inducible factors (HIFs) to facilitate adaptation to low oxygen environments is well-characterized; however, post-transcriptional regulation by microRNAs (miRNAs) is poorly understood. Here, we investigated the mRNA and miRNA response in hypoxia-mediating reduced growth and cellular metabolism. Next-generation sequencing revealed the impact of hypoxia in cultured human hepatocellular carcinoma cells and identified over 400 mRNAs and 140 miRNAs that were differentially expressed. Hypoxia upregulated mRNA transcripts associated with glycolysis, DNA replication and the PI3K (phosphoinositide 3-kinase)-Akt pathway, which promote anaerobic metabolism for energy production, decreased cell proliferation and genomic instability, respectively. Upregulated miRNAs included miR-197-3p and miR-766-3p, targeting genes involved in lipid biosynthesis and metabolism. Downregulated miRNAs included miR-33a-5p and miR-15a-5p, targeting genes involved in glycolysis and lactate metabolism. Notably, miR-6834 emerged as a potential regulator of mechanistic target of rapamycin (mTOR) signaling and insulin-like growth factor binding protein-1 (IGFBP-1) signaling; miR-6834 overexpression altered 4E-BP1 phosphorylation levels and IGFBP-1 secretion. These findings provide critical insights into miRNA–mRNA regulation of metabolic adaptation and highlight miRNAs as potential targets for interventions with relevance to tumor biology and other hypoxia-associated conditions. Full article

In this study, emodin was used as the starting material to synthesize two novel ligands, L1 and L2, containing bipyridine or phenanthroline moieties. Seven metal complexes (1–7) were obtained through coordination with Co, Rh, Ru, and Pt ions. Their structures were confirmed via NMR, HRMS, UV–Vis, IR, HPLC and SC-XRD analyses. The MTT assay showed that L1 and complex 2 selectively inhibited HepG-2 cells, with IC₅₀ values of 8.77 μM and 6.10 μM, respectively. Both compounds exhibited stronger activity than cisplatin (9.05 μM) and low toxicity toward normal 293T cells. Mechanistic studies demonstrated that they induced G2/M phase arrest by regulating Cyclin B1 and P21 expression, which was accompanied by ROS and Ca²⁺ accumulation, mitochondrial membrane potential disruption, and activation of the Caspase-9/3 cascade. Complex 2 showed superior antitumor activity to L1, and this finding was further supported by molecular docking analysis. In sum, Rh(III) complex 2 was identified as a selective and mechanistically defined anti-hepatocellular carcinoma lead compound, providing a potential strategy for the development of natural product-based metal anticancer agents. Full article

Hepatocellular carcinoma (HCC) lacks effective early diagnostic markers and is heavily driven by angiogenesis and hypoxia. Emerging evidence indicates that metabolic enzymes and noncoding RNAs coordinate these processes. Here, we reveal that phosphoserine phosphatase (PSPH), a serine biosynthesis enzyme, is significantly upregulated in HCC, correlating with angiogenic markers and poor prognosis. Clinical data and functional assays demonstrated that miR-101-3p directly targets the PSPH 3′ UTR to suppress its expression, while lncRNA GSEC acts as a competing endogenous RNA to sponge miR-101-3p. In vitro, GSEC knockdown or miR-101-3p overexpression decreased PSPH and HIF1α levels, strongly inhibiting HCC angiogenesis, migration, invasion, and proliferation. Crucially, these anti-tumor effects were reversed by restoring PSPH. In vivo, modulating the GSEC/PSPH axis significantly altered xenograft tumor growth and vascularization. Conclusively, the GSEC/miR-101-3p/PSPH regulatory axis drives HIF1α-dependent angiogenesis and HCC progression, highlighting PSPH as a promising diagnostic biomarker and therapeutic target. Full article

Background: Hepatocellular carcinoma (HCC) is the predominant histological subtype of primary liver cancer, and many patients with unresectable disease require systemic therapy. This narrative review asks how current systemic regimens should be selected and sequenced, how oncogenic pathways inform resistance and biomarker development, and which emerging platforms have sufficient evidence for clinical translation. Methods: We synthesized key oncogenic pathways, pivotal trials, major guidelines, and selected translational studies cited in this review. Randomized phase III evidence was prioritized for clinical claims, whereas observational, early-phase, and preclinical studies were used to define evidence gaps and emerging approaches. Results: Immune-based combinations have reshaped first-line treatment for advanced HCC. Treatment selection must account for liver function, performance status, bleeding risk, and contraindications to anti-VEGF or immune checkpoint therapy. Evidence for post-immunotherapy sequencing remains largely observational, and validated predictive biomarkers are scarce. Conclusions: Future progress requires prospective sequencing studies, biomarker-enriched trials, and rigorous early-phase evaluation of cell, antibody, gene-editing, viral, and nanodelivery platforms. Full article

Hepatocellular carcinoma (HCC) is an aggressive liver cancer requiring reliable biomarkers, while current approaches are limited by high-dimensional data and complex nonlinear gene interactions. In this study, differentially expressed genes were identified and fed to a deep autoencoder to reduce dimensionality, capture nonlinear interactions, and extract informative latent features. Predictive gene features were selected through mutual information (MI) ranking and LASSO regression and subsequently evaluated using logistic regression (LR), random forest (RF), and support vector machine (SVM) classifiers with 5-fold cross-validation (CV). The top 50 genes underwent enrichment analyses. Protein–protein interaction (PPI) networks were constructed to identify hub genes, followed by gene–drug interaction, transcription factor analysis, and survival validation. Enrichment analysis highlighted critical pathways involved in metabolic, signaling, and cell-cycle, and viral carcinogenesis. CV showed stable and high performance across classifiers (accuracy = 0.969, F1 ≈ 0.97), with RF and SVM achieving the highest AUC values (~0.983 and ~0.982). Independent tests showed excellent performance, with RF achieving perfect performance (1.0) across all evaluation metrics, confirming high feature discriminative power. Survival analysis showed that hub genes, including HSP90AB1, TUBA1B, PKM, H2AZ1, YWHAZ, ACLY, RAN, ILF2, KPNA2, and TXNRD1, were significantly associated with poor prognosis (HR > 1.5, p < 0.05), correlating with reduced overall, relapse-free, and disease-specific survival in HCC. The integrative novel framework effectively identifies biologically relevant biomarkers, providing insights into HCC mechanisms and potential targets for precision therapy. 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

Background/Objectives: The 2026 Barcelona Clinic Liver Cancer (BCLC) update recommends surgical resection for a single hepatocellular carcinoma larger than 2 cm with preserved liver function and states that age alone should not preclude surgery. How often eligible older patients undergo resection, and how they fare, remains unquantified. Methods: Using the Korean Primary Liver Cancer Registry (2008–2021), we identified 3374 patients meeting all registry-based eligibility criteria of the 2026 BCLC update. Survival was measured from the date of radiological diagnosis in every patient, with vital status and cause of death obtained by linkage to national death records. We compared use of resection and survival among patients younger than 75 years and those 75 years or older, and across resection, ablation, other treatment, and no treatment, using Cox regression, restricted mean survival time (RMST), and competing-risk models. Results: Resection was performed in 60.6% of patients younger than 75 years versus 28.9% of those 75 years or older (p < 0.001); among older patients not undergoing resection, 21.5% received none. Older age was independently associated with lower odds of resection (adjusted odds ratio 0.36, 95% CI 0.28–0.46; p < 0.001). In this age group, 5-year survival was 61.3%, 62.1%, 32.9%, and 6.5% across the four treatment categories; the adjusted hazard ratio for no treatment versus resection was 4.97 (95% CI 3.26–7.57; p < 0.001). In unadjusted analysis, mean survival within the first 5 years was 13.3 months longer after resection (RMST difference, 95% CI 9.7–16.9; p < 0.001). Findings were consistent in competing-risk, weighted, cirrhosis-adjusted, and multiply imputed analyses. Conclusions: Older patients meeting eligibility criteria underwent resection far less often than younger patients, and a substantial minority received none, a pattern associated with markedly shorter survival. Full article