Search Results (401)

This study explores how aristolochic acid I (AAI) drives hepatocellular carcinoma (HCC). We first employ network toxicology and machine learning to map the key molecular target genes. Next, our research utilizes molecular docking to evaluate how AAI binds to these targets, and finally confirms the stability and dynamics of the resulting complexes through molecular dynamics simulations. We identified 193 overlapping target genes between AAI and HCC through databases such as PubChem, OMIM, and ChEMBL. Machine learning algorithms (SVM-RFE, random forest, and LASSO regression) were employed to screen 11 core genes. LASSO serves as a rapid dimension-reduction tool, SVM-RFE recursively eliminates the features with the smallest weights, and Random Forest achieves ensemble learning through decision trees. Protein–protein interaction networks were constructed using Cytoscape 3.9.1, and key genes were validated through GO and KEGG enrichment analyses, an immune infiltration analysis, a drug sensitivity analysis, and a survival analysis. Molecular-docking experiments showed that AAI binds to each of the core targets with a binding affinity stronger than −5 kcal mol⁻¹, and subsequent molecular dynamics simulations verified that these complexes remain stable over time. This study determined the potential molecular mechanisms underlying AAI-induced HCC and identified key genes (CYP1A2, ESR1, and AURKA) as potential therapeutic targets, providing valuable insights for developing targeted strategies to mitigate the health risks associated with AAI exposure. Full article

Background/Objectives: Primary liver cancer (PLC), encompassing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), constitutes a growing global health concern. Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) and Type 2 diabetes mellitus (T2DM) represent a recurrent epidemiological overlap. Individuals with MASLD and T2DM (MASLD-T2DM) are at a higher risk of PLC. This scoping review highlights the epidemiological burden, the classic and novel pathogenetic frontiers, and the potential strategies optimizing the management of PLC in MASLD-T2DM. Methods: A systematic search of the PubMed, Medline, and SCOPUS electronic databases was conducted to identify evidence investigating the pathogenetic mechanisms linking MASLD and T2DM to hepatic carcinogenesis, highlighting the most relevant targets and the relatively emerging therapeutic strategies. The search algorithm included in sequence the filter words: “MASLD”, “liver steatosis”, “obesity”, “metabolic syndrome”, “body composition”, “insulin resistance”, “inflammation”, “oxidative stress”, “metabolic dysfunction”, “microbiota”, “glucose”, “immunometabolism”, “trained immunity”. Results: In the MASD-T2DM setting, insulin resistance (IR) and IR-induced mechanisms (including chronic inflammation, insulin/IGF-1 axis dysregulation, and autophagy), simultaneously with the alterations of gut microbiota composition and functioning, represent crucial pathogenetic factors in hepatocarcinogenesis. Besides, the glucose-related metabolic reprogramming emerged as a crucial pathogenetic moment contributing to cancer progression and immune evasion. In this scenario, lifestyle changes, simultaneously with antidiabetic drugs targeting IR-related effects and gut-liver axis, in parallel with novel approaches modulating immunometabolic pathways, represent promising strategies. Conclusions: Metabolic dysfunction, classically featuring MASLD-T2DM, constitutes a continuously expanding global issue, as well as a critical driver in PLC progression, demanding integrated and personalized interventions to reduce the future burden of disease. Full article

Background: Hepatocellular carcinoma (HCC) is one of the most common and fatal malignancies worldwide, characterized by remarkable molecular heterogeneity and poor clinical outcomes. Despite advancements in diagnosis and treatment, the prognosis for HCC remains dismal, largely due to late-stage diagnosis and limited therapeutic efficacy. Therefore, there is a critical need to identify novel therapeutic targets and explore alternative strategies, such as drug repurposing, to improve patient outcomes. Methods: In this study, we employed network pharmacology, molecular docking, and molecular dynamics (MD) simulations to explore the potential therapeutic targets of Nirmatrelvir in HCC. Results: Nirmatrelvir targets were predicted through SwissTarget (101 targets), SuperPred (1111 targets), and Way2Drug (38 targets). Concurrently, HCC-associated genes (5726) were retrieved from DisGeNet. Cross-referencing the two datasets identified 29 overlapping proteins. A protein–protein interaction (PPI) network constructed from the overlapping proteins was analyzed using CytoHubba, identifying 10 hub genes, with HDAC1, HDAC3, and STAT3 achieving the highest degree scores. Molecular docking revealed a strong binding affinity of Nirmatrelvir to HDAC1 (docking score = −7.319 kcal/mol), HDAC3 (−6.026 kcal/mol), and STAT3 (−6.304 kcal/mol). Moreover, Nirmatrelvir displayed stable dynamic behavior in repeated 200 ns simulation analyses. Binding free energy calculations using MM/GBSA showed values of −23.692 kcal/mol for the HDAC1–Nirmatrelvir complex, −33.360 kcal/mol for HDAC3, and −21.167 kcal/mol for STAT3. MM/PBSA analysis yielded −17.987 kcal/mol for HDAC1, −27.767 kcal/mol for HDAC3, and −16.986 kcal/mol for STAT3. Conclusions: The findings demonstrate Nirmatrelvir’s strong binding affinity towards HDAC3, underscoring its potential for future drug development. Collectively, the data provide computational evidence for repurposing Nirmatrelvir as a multi-target inhibitor in HCC therapy, warranting in vitro and in vivo studies to confirm its clinical efficacy and safety and elucidate its mechanisms of action in HCC. Full article

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive disease that easily develops into cirrhosis and hepatocellular carcinoma, but its pathogenesis is not clear, and most therapeutic drugs have obvious limitations. However, Babao Dan (BBD) has a good therapeutic effect on liver disease, but its treatment mechanism is still to be studied. Therefore, we further investigated the mechanism of BBD in treating MASH. Methods: We predicted BBD-related targets through network pharmacology and further verified the binding ability of BBD-related targets through molecular docking. We also detected relevant indicators before and after model treatment, as well as metabolomics analysis and identification of the mechanism of action of BBD on MASH. Results: Through network pharmacology methods, 158 key cross targets and the top 10 core targets were identified, and it was determined that the PI3K-AKT signaling pathway plays an important regulatory role in the treatment of MASH with BBD. The molecular docking results indicate that the representative compounds quercetin and 17 Beta Estradiol have good binding activity with five core targets. Metabolomics has identified four metabolic biomarkers, such as Piceid, and it is determined that the key pathway for BBD treatment of MASH is the bile secretion pathway. Conclusions: BBD effectively treats MASH by modulating Piceid and other biomarkers, targeting ESR1 and other core proteins via quercetin and 17-beta-estradiol, and regulating the PI3K-AKT and bile secretion pathways to alleviate liver injury. Full article

Background/Objectives: Hepatocellular carcinoma (LIHC) poses significant challenges due to limited targeted therapeutic options. This study investigates SMYD5, an oncogene implicated in the pathogenesis of LIHC, and its interaction with the BRD4 protein. Methods: We employed bioinformatics analyses alongside experimental validations to assess SMYD5 expression across various cancers, particularly LIHC. This included survival analysis, protein expression studies, and functional assays to understand the role of SMYD5 in LIHC progression. Results: Our findings demonstrate that SMYD5 expression is markedly elevated in LIHC tumor tissues compared to normal liver tissues. Moreover, high levels of SMYD5 correlate with poor overall survival and disease-free survival rates in LIHC patients. Functional assays indicate that the knockdown of SMYD5 significantly inhibits cell proliferation and increases apoptosis in LIHC cell lines. Additionally, a notable interaction between SMYD5 and BRD4 was identified, suggesting a potential therapeutic target in the SMYD5-BRD4 axis. Conclusions: These findings collectively establish SMYD5 as a molecular driver in LIHC pathology and identify the SMYD5-BRD4 interaction axis as a promising therapeutic target for future drug development. Full article

Background and Objectives: VPS26A, a core component of the retromer complex, is pivotal to endosomal trafficking and membrane protein recycling. However, its expression profile, prognostic significance, and clinical relevance in liver hepatocellular carcinoma (LIHC) remain unexplored. This study investigates the prognostic potential of VPS26A by extensively analyzing publicly available LIHC-related databases. Materials and Methods: Multiple databases, including TIMER, UALCAN, HPA, GSCA, KM Plotter, OSlihc, MethSurv, miRNet, OncomiR, LinkedOmics, GeneMANIA, and STRING, were used to evaluate VPS26A expression patterns, prognostic implications, correlations with tumor-infiltrating immune cells (TIICs), epigenetic modifications, drug sensitivity, co-expression networks, and protein–protein interactions in LIHC. Results: VPS26A was significantly overexpressed at both the mRNA and protein levels in LIHC tissues compared to that in normal tissues. This upregulation was strongly associated with a poor prognosis. Furthermore, VPS26A expression was both positively and negatively correlated with various TIICs. Epigenetic analysis indicated that VPS26A is regulated by promoter and regional DNA methylation. Additionally, VPS26A influences the sensitivity of LIHC cells to a broad range of anticancer agents. Functional enrichment and co-expression analyses revealed that VPS26A serves as a central regulator of the LIHC transcriptomic landscape, with positively correlated gene sets linked to poor prognosis. Additionally, VPS26A contributes to the molecular architecture governing vesicular trafficking, with potential relevance to diseases involving defects in endosomal transport and autophagy. Notably, miRNAs targeting VPS26A-associated gene networks have emerged as potential prognostic biomarkers for LIHC. VPS26A was found to be integrated into a highly interconnected signaling network comprising proteins in cancer progression, immune regulation, and cellular metabolism. Conclusions: Overall, VPS26A may serve as a potential prognostic biomarker and therapeutic target in LIHC. This study provides novel insights into the molecular mechanisms underlying LIHC progression, and highlights the multifaceted role of VPS26A in tumor biology. Full article

Background: Tumor-associated macrophages (TAMs) are critical regulators of the hepatocellular carcinoma (HCC) microenvironment, yet their epigenetic heterogeneity and regulatory programs remain poorly defined. Methods: We performed integrative analysis on single-cell RNA-seq and ATAC-seq profiling of HCC patients to dissect TAM subtypes at high resolution. By correlating chromatin accessibility with gene expression, we identified cell-type-specific candidate cis-regulatory elements (CREs). TAM subsets with prognostic significance were determined through integration with HCC clinical cohorts. Pseudotime and multi-regional analyses were used to uncover regulatory trajectories underlying macrophage phenotypic transitions. The identification framework of a super-enhancer (SE) was constructed, and potential therapeutic targets were prioritized using drug–gene interaction data. Results: We delineated the regulatory landscape of TAMs in HCC, revealing cell-type-specific chromatin accessibility patterns underlying TAM heterogeneity. The 65,342 CREs linked to gene expression were identified, with distal CREs contributing most to cell-type-specific regulation. Notably, SPP1⁺ TAMs were found to be enriched in tumor cores and associated with poor prognosis in HCC. Liver-resident Kupffer cells showed progressive loss of the core transcription factors SPIC and MAFB, suggesting a potential transition into SPP1⁺ TAMs under tumor pressure. We identified 133 SPP1⁺ TAM-specific SEs and constructed a TF–SE–target gene regulatory network. Notably, 13 target genes showed higher drug–gene interaction effects, highlighting their therapeutic potential. Conclusions: This study provides the chromatin accessibility map of TAMs in HCC and reveals how distal CRE-driven transcriptional programs shape TAM states. Our findings lay the foundation for understanding the epigenetic regulation of TAM heterogeneity and nominate potential targets for TAM-directed immunotherapy in HCC. Full article

(1) Background: Hepatocellular carcinoma (HCC) is a major global health issue, ranking among the most frequently diagnosed cancers and one of the leading causes of cancer-related mortality. (2) Methods: To identify studies that focus on nanotechnology-mediated treatment and early diagnosis in hepatocellular carcinoma, our group conducted a thorough literature search across major scientific databases. (3) Results: In this narrative review, we demonstrated that nanotechnology—particularly the use of nanoparticles—holds significant potential for both the treatment and early detection of hepatocellular carcinoma. Nanoparticles act as carriers for the targeted delivery of drugs to cancer cells, greatly enhancing treatment efficacy while minimizing adverse effects on healthy tissues. Due to their physicochemical properties, these nanoparticles can also carry contrast agents, enabling precise identification of tumor cells and contributing to the early diagnosis of hepatocellular carcinoma. (4) Conclusions: While significant progress has been made, challenges such as toxicity, cost, and regulatory hurdles remain. Full article

Anthracyclines have been clinically well established in cancer chemotherapy for decades. The main limitations of this drug class are the development of resistance and severe side effects. In the present investigation, we analyzed 30 anthracyclines in a panel of 59 cell lines of the National Cancer Institute, USA. The log₁₀IC₅₀ values varied from −10.49 M (3′-deamino-3′-(4″-(3″-cyano)morpholinyl)-doxorubicin, 1) to −4.93 M (N,N-dibenzyldaunorubicin hydrochloride, 30). Multidrug-resistant NCI-ADR-Res ovarian cancer cells revealed a high degree of resistance to established anthracyclines (between 18-fold to idarubicin (4) and 166-fold to doxorubicin (13) compared to parental, drug-sensitive OVCAR8 cells). The resistant cells displayed only low degrees of resistance (1- to 5-fold) to four other anthracyclines (7, 18, 28, 30) and were even hypersensitive (collaterally sensitive) to two compounds (1, 26). Live cell time-lapse microscopy proved the cross-resistance of the three chosen anthracyclines (4, 7, 9) on sensitive CCRF/CEM and multidrug-resistant CEM/ADR5000 cells. Structure–activity relationships showed that the presence of tertiary amino functions is helpful in avoiding resistance, while primary amines rather increased resistance development. An α-aminonitrile function as in compound 1 was favorable. Investigating the mRNA expression of 49 ATP-binding cassette (ABC) transporter genes showed that ABCB1/MDR1 encoding P-glycoprotein was the most important one for acquired and inherent resistance to anthracyclines. Molecular docking demonstrated that all anthracyclines bound to the same binding domain at the inner efflux channel side of P-glycoprotein with high binding affinities. Kaplan–Meier statistics of RNA sequencing data of more than 8000 tumor biopsies of TCGA database revealed that out of 23 tumor entities high ABCB1 expression was significantly correlated with worse survival times for acute myeloid leukemia, multiple myeloma, and hepatocellular carcinoma patients. This indicates that ABCB1 may serve as a prognostic marker in anthracycline-based chemotherapy regimens in these tumor types and a target for the development of novel anthracycline derivatives. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), the leading chronic liver condition globally, constitutes a major etiological contributor to hepatocellular carcinoma (HCC). Its transition from steatosis to non-alcoholic steatohepatitis (NASH) involves progressive fibrosis, ultimately predisposing to HCC. The pathogenesis involves multifactorial interactions among genetic susceptibility, environmental triggers, and obesity-associated metabolic dysregulation. Crucially, the gut–liver axis serves as a pivotal regulatory mechanism in MASLD development. Current therapeutic strategies prioritize lifestyle interventions for metabolic syndrome management, while pharmacological options remain limited, underscoring the need for new therapies. Emerging evidence highlights phenolic acids—bioactive phytochemicals from medicinal plants—as multi-target agents against MASLD. These compounds demonstrate therapeutic efficacy via antioxidative modulation of stress, anti-inflammatory activity, and gut–liver axis regulation. This review synthesizes recent advances in natural phenolic acids for MASLD intervention, emphasizing their potential as preventive and therapeutic candidates. Their multimodal mechanisms may inform innovative drug development paradigms targeting MASLD pathogenesis. Full article

Hepatocellular carcinoma (HCC) is still a leading cause of cancer-related mortality worldwide, characterized by poor prognosis and limited therapeutic efficacy of conventional chemotherapeutics such as doxorubicin. Phytochemicals are promising adjuvants in cancer therapy due to their multi-targeted effects. In this in vitro study, we investigated the impact of a methanol–water extract (70:30 v/v, MET70) from Muscari comosum bulbs, rich in polyphenols and flavonoids, on doxorubicin-treated HepG2 human hepatoma cells. Co-treatment with MET70 increased intracellular reactive oxygen species (ROS) associated with downregulation of Nrf2 signaling, suppression of antioxidant enzymes (SOD2, GPX-1) and decreased mitochondrial UCP2 expression. MET70 modulated the inflammatory response induced by doxorubicin by decreasing TNF-α and increasing IL-6 expression. MET70 also promoted protein homeostasis through PDIA2 upregulation without exacerbating endoplasmic reticulum stress and inhibited autophagy by reducing Beclin-1 levels, contributing to increased chemosensitivity. Moreover, MET70 downregulated ABCC1 expression, suggesting a role in overcoming multidrug resistance. All these findings demonstrate that Muscari comosum extract enhances doxorubicin efficacy by targeting redox balance, inflammatory signaling, autophagy, and drug resistance, offering a promising redox-based strategy for improving HCC therapy. However, further studies should be performed in vivo. Full article

Hepatitis C virus (HCV) remains a global health challenge, contributing to chronic liver disease and hepatocellular carcinoma. In Thailand, HCV prevalence has declined from ~2% in the 1990s due to universal blood screening, harm reduction, and expanded treatment. This narrative review draws on diverse sources—including PubMed and Scopus databases, international and national health websites, government reports, and local communications—to compile epidemiological data, genotype distribution, and elimination strategies, with a focus on Phetchabun province, Thailand, as a model for achieving the World Health Organization’s (WHO) hepatitis C elimination targets. National surveys in 2004, 2014, and 2024 show a prevalence drop from 2.15% to 0.56%. However, HCV persists among high-risk groups, including people who inject drugs, people living with HIV, patients undergoing maintenance hemodialysis, and prisoners. Thailand’s National Health Security Office has expanded treatment access, including universal screening for those born before 1992. The Phetchabun Model, launched in 2017, employs a decentralized test-to-treat strategy. By April 2024, 88.64% (288,203/324,916) of the target population was screened, and 4.88% were anti-HCV positive. Among those tested, 72.61% were HCV-RNA positive, and 88.17% received direct-acting antivirals (i.e., SOF/VEL), achieving >96% sustained virological response. The Phetchabun Model demonstrates a scalable approach for HCV elimination. Addressing testing costs, improving access, and integrating microelimination strategies into national policy are essential to achieving the WHO’s 2030 goals. Full article

The increasing prevalence of liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD), presents considerable medical challenges, particularly given the absence of approved pharmacological treatments, which underscores the necessity to comprehend its underlying mechanisms. Extracellular vesicles (EVs), which are tiny particles released by cells, play a crucial role in facilitating communication and can transport harmful molecules that promote inflammation and tissue damage. These EVs are involved in the progression of various types of liver disorders since they aggravate inflammation and oxidative stress. Because of their critical role, it is believed that EVs are widely involved in the initiation and progression of MASLD, as well as in viral hepatitis, alcoholic liver disease, drug-induced liver injury, and hepatocellular carcinoma. This review emphasizes recent findings regarding the functions of EVs in the above liver pathologies and underscores their potential as new therapeutic targets, paving the way for innovative approaches to address those detrimental liver conditions. Full article

Hepatocellular carcinoma (HCC) is an aggressive and prevalent liver cancer with a poor prognosis. Nanotechnology combined with natural products has emerged as a promising strategy to enhance HCC treatment efficacy. This review assesses the current literature on the application of nanotechnology in delivering natural products for HCC therapy. A comprehensive search was conducted in PubMed, Science Direct, Web of Science, and Google Scholar to identify relevant studies published up to the present articles focusing on nanotechnology-based drug delivery systems using natural products for HCC therapy, including different nanoparticle (NP) formulations and therapeutic interventions, were included. Natural products with anticancer properties have been encapsulated using various nanocarriers such as liposomes, polymeric nanoparticles, and quantum dots, which have improved drug stability, prolonged circulation time, and enhanced targeted delivery to HCC cells. These advancements have led to increased therapeutic efficacy and reduced side effects. Additionally, combining multiple natural products or integrating them with conventional therapies via nanocarriers enables personalized treatment approaches based on patient characteristics and molecular profiles. The integration of nanotechnology with natural products shows great potential for improving HCC treatment outcomes, representing a significant advancement in precision medicine for liver cancer and paving the way for more effective and personalized therapeutic strategies. Full article

Hepatocellular carcinoma remains one of the leading contributors to global cancer mortality, frequently stemming from chronic liver conditions, such as viral hepatitis, non-alcoholic fatty liver disease, and alcohol-induced cirrhosis. While antiviral treatments have made significant strides, the rising prevalence of hepatocellular carcinoma linked to non-infectious causes underscores the pressing demand for more effective diagnostic tools and therapeutic interventions. Advances in imaging and liquid biopsy technologies have facilitated early detection and diagnosis, and treatment strategies are diversifying to include immune checkpoint inhibitors, tyrosine kinase inhibitors, and interventional therapies. Translational therapies for advanced hepatocellular carcinoma have improved surgical opportunities and patient survival. Artificial intelligence has played a transformative role in the diagnosis and treatment of hepatocellular carcinoma, in terms of image analysis, histopathologic classification, drug development, and targeted therapy. The future of hepatocellular carcinoma treatment lies in precision oncology and the collaboration of multidisciplinary teams, as well as in early detection. The ultimate goal is to keep patients alive longer and reduce the global burden of this complex malignancy. Full article