Search Results (1,521)

Metabolic rewiring is a hallmark of both hepatic regeneration and malignant transformation, complicating the identification of cancer-specific traits. This study aimed to distinguish the metabolic profiles of proliferating hepatocytes and hepatocellular carcinoma (HCC) cells through integrated analyses of mRNA and protein expression, along with functional characterization. We compared non-malignant Upcyte^® hepatocytes (HepaFH3) cultured under proliferative and confluent conditions with primary human hepatocytes, primary human hepatoma cells, and hepatoma cell lines. Proliferating HepaFH3 cells exhibited features of metabolic reprogramming, including elevated glycolysis, increased HIF1A expression, and ketone body accumulation, while maintaining low c-MYC expression and reduced BDH1 levels, distinguishing them from malignant models. In contrast, HCC cells showed upregulation of HK2, c-MYC, and BDH1, reflecting a shift toward aggressive glycolytic and ketolytic metabolism. Functional assays supported the transcript and protein expression data, demonstrating increased glucose uptake, elevated lactate secretion, and reduced glycogen storage in both proliferating and malignant cells. These findings reveal that cancer-like metabolic changes also occur during hepatic regeneration, limiting the diagnostic utility of individual metabolic markers. HepaFH3 cells thus provide a physiologically relevant in vitro model to study regeneration-associated metabolic adaptation and may offer insights that contribute to distinguishing regenerative from malignant processes. Our findings highlight the potential of integrated metabolic profiling in differentiating proliferation from tumorigenesis. Full article

Hepatocellular carcinoma (HCC) is the most common liver cancer, with poor survival rates in advanced stages due to late diagnosis, tumor heterogeneity, and therapy resistance. The tumor microenvironment (TME) in HCC has a crucial role in tumor progression, characterized by a complex interaction of immune cells, stromal components, and immunosuppressive signaling pathways. Chronic inflammation driven by viral infections, metabolic dysfunction, and alcohol consumption triggers an immunosuppressive TME, promoting immune evasion and tumor growth. Immune cell populations, such as myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages, contribute to immunosuppression, while cytotoxic T lymphocytes and natural killer cells exert anti-tumor effects. Recent advances in immunotherapy, mainly immune checkpoint inhibitors (ICIs) targeting programmed death-ligand 1 and programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4, have revolutionized HCC treatment, though response rates remain limited. Combined therapies using tyrosine kinase inhibitors, anti-angiogenic agents, and ICIs improve patient outcomes. This review discusses the immunological mechanisms contributing to HCC progression, the role of immune cell subsets in tumor evasion, and therapeutic interventions, from conventional treatments to advanced immunotherapies. Ongoing clinical trials, barriers to effective treatment, and future directions to enhance HCC management and patient survival will also be overviewed. Full article

The liver’s susceptibility to age-related diseases, including hepatocellular carcinoma (HCC), is increasingly linked to progressive epigenetic alterations that disrupt gene regulation, promote fibrosis, and impair regeneration. While glucagon-like peptide-1 receptor agonists (GLP-1RAs) are well-established in the treatment of type 2 diabetes and obesity, emerging evidence suggests they may also exert protective effects on the liver through the modulation of epigenetic pathways. In this perspective, we explore the hypothesis that GLP-1RAs may help restore a healthier epigenetic state in the aging liver by influencing mechanisms such as DNA methylation, histone modification, and non-coding RNA activity. These effects could reduce chronic inflammation, hepatic stellate cell activation, and fibrotic remodeling, key steps in the path to HCC. Preclinical studies have shown GLP-1RAs can affect transcriptional regulation and fibrotic markers, and early clinical data support improvements in liver function and structure in patients with metabolic liver disease. We highlight the need for further research to clarify these mechanisms in aging populations and propose that GLP-1RAs hold potential as a novel therapeutic strategy to reduce liver cancer risk by targeting the epigenetic contributors to disease progression. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and currently is the second-leading cause of cancer-related mortality globally. Current front-line systemic therapies for advanced HCC offer only modest improvements in patient overall survival. HCC is a sexually dimorphic disease, and cancer progression is driven in part by AR activity. Here, we present novel niclosamide pro-drugs for use in advanced HCC based upon niclosamide’s known anti-AR activity and additional anti-cancer pathway efficacy. Methods: Niclosamide analogs were evaluated for their impacts on the AR protein in two HCC cell lines with different AR phenotypes. Amino acid conjugates of niclosamide were developed, and pharmacokinetic (PK) analyses were conducted to determine improvements in clearance and oral exposure. Finally, niclosamide analogs and amino acid conjugates were evaluated in an in vivo model of HCC. Results: Niclosamide analogs maintained anti-AR properties in HCC. Valine-conjugated niclosamide showed improved oral exposure, positioning it as a potential therapeutic in advanced HCC. Conclusions: Valine–niclosamide improves upon niclosamide’s poor solubility and oral bioavailability, increasing its utility for a variety of therapeutic uses. Further study of valine–niclosamide in advanced HCC and in other cancers or diseases is warranted. Full article

Approximately 90% of liver cancer cases are classified as hepatocellular carcinomas (HCCs), with chemotherapy and immunotherapy being the most recommended treatment options. While conventional chemotherapy specifically targets rapidly dividing cancer cells, it can also impact on healthy cells that are proliferating quickly. This collateral damage to healthy cells, along with the potential for cancer cells to develop resistance, presents significant challenges for conventional chemotherapy in liver cancer patients. Hepatic artery infusion of chemotherapy (HAIC) generally leads to reduced toxicity and fewer side effects. The process of catheter insertion is usually performed under local anesthesia, with lidocaine being the preferred choice to combine with various chemotherapeutics in HCC treatment. In our study, we explored the effects of repurposing lidocaine in combination with cisplatin or 5-fluorouracil (5-FU) on two HCC cell lines, HepG2 and Hep3B. Our cytotoxicity analysis revealed that lidocaine functions as a chemosensitizer for cisplatin and 5-FU in both HepG2 and Hep3B cells. Specifically, we observed an increase in the subG1 population and a reduction in cytosolic reactive oxygen species in cisplatin- or 5-FU-treated HepG2 and Hep3B cells. Interestingly, lidocaine selectively decreased the reduced/oxidized glutathione ratio in cisplatin- or 5-FU-treated HepG2 cells but not in Hep3B cells. Furthermore, lidocaine induced endoplasmic reticulum stress, apoptosis, mitochondrial membrane depolarization, lipid peroxidation, and autophagy while suppressing cellular proliferation HepG2 and Hep3B cells. In conclusion, our study demonstrates the synergistic potential of combining lidocaine with cisplatin or 5-FU for the treatment of HCC, indicating that lidocaine may serve as an effective chemosensitizer. These findings highlight a new clinical advantage of using repurposing lidocaine as a chemosensitizer in the current HAIC procedure, suggesting that this combination warrants further exploration through rigorous clinical trials. In the future, we can better optimize therapeutic regimens, potentially leading to improved patient outcomes in HCCs. Full article

Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to metabolic plasticity and drug resistance. Oncolytic viruses (OVs), such as thymidine kinase-deleted vaccinia virus (oncoVV), selectively lyse tumors while stimulating antitumor immunity, however, their metabolic interplay with cancer cells is poorly understood. Here, we engineered an oncoVV-expressing Aphrocallistes vastus lectin (oncoVV-AVL) and uncovered its unique ability to exploit the ACSS2/TFEB axis, driving metabolic competition in HCC. In vitro, oncoVV-AVL triggered cell autophagy and lipid accumulation (3.4–5.7-fold upregulation of FASN and ACC1) while suppressing glucose uptake (41–63% higher extracellular glucose and 33–34% reduced lactate). Mechanistically, oncoVV-AVL upregulated acetyl-CoA synthetase 2 (ACSS2), promoting its nuclear translocation and interaction with transcription factor EB (TFEB) to concurrently activate lipogenesis and autophagic flux. The pharmacological inhibition of ACSS2 abolished these effects, confirming its central role. In vivo, oncoVV-AVL suppressed tumor growth while inducing lipid deposition (2-fold triglyceride increase), systemic hypoglycemia (42% glucose reduction), and autophagy activation (elevated LC3B-II/I ratios). This study establishes ACSS2 as a metabolic checkpoint in OV therapy, providing a rationale for combining oncolytic virotherapy with metabolic modulators in HCC. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently become the leading cause of chronic liver disease and can progress to hepatocellular carcinoma (HCC) through multiple pathogenic mechanisms. Protease-activated receptor 2 (PAR2) is a G-protein-coupled receptor activated by proteases such as trypsin, tryptase or coagulation factors VII and Xa. Recent studies have shown that PAR2 expression is increased in the liver of patients with MASLD or liver fibrosis. Its activation is linked to metabolic dysfunction through several pathways, including SREBP1c activation, AMPK inhibition and Akt-induced insulin resistance. Inhibition of PAR2 has been effective in reducing MASLD progression in different animal models. Notably, PAR2 blockade has also been effective in more advanced stages of the disease by dampening chronic inflammation and fibrogenesis through the inhibition of hepatic stellate cell activation and of TGF-β and SerpinB3 production. PAR2 also plays a role in cancer development, promoting tumour proliferation, angiogenesis and expression of immune checkpoint inhibitors (like PD-L1, CD47 and CD24). Due to its multifaceted involvement in liver disease, PAR2 is emerging as a key therapeutic target in this clinical context. This review aims to summarise current knowledge on PAR2′s role in MASLD and its potential as a therapeutic target. Full article

Hepatocellular carcinoma (HCC) is a malignancy with a complex pathogenesis, course, and prognosis with increasing incidence. The most significant contributing factor to the development of HCC is the chronic process of inflammation and remodeling of the cirrhotic liver, in which the interaction between the tumor microenvironment (TME) and cancer cells plays a pivotal role. In recent years, increasing focus has been directed toward the role of platelets (PLTs) in mediating interactions between tumor cells and the TME and in the progression and spread of HCC, as well as other cancers. Due to their abundance in the bloodstream and intracellular granules rich in mediators facilitating their ability to modulate the immune system, PLTs play a significant role in carcinogenesis. In the context of HCC, the role of PLTs in the healing and regeneration processes of the liver has been recognized for some time. In recent years, there has been an increasing utilization of PLTs in prognostic models for patients with HCC. Given their role and the availability of clinical options that block PLTs’ action, clinical trials of platelet blockers in the adjunctive treatment of HCC are becoming increasingly common. However, further research, both preclinical and clinical, is necessary to fully elucidate the role of PLTs in HCC and their potential use as a therapeutic target. In this literature review, we summarize the current knowledge on PLTs in HCC and focus on their potential use in everyday clinical practice. Full article

Background: Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), and the metabolic activities of both tumor cells and TAMs have an impact on the TME. Moreover, the expression of MICA in tumor cells is closely associated with immune cells in hepatocellular carcinoma (HCC). However, it remains unclear whether MICA expression correlates with TAMs and influences the switch in macrophage phenotype by mediating metabolic alterations. Methods: Various biostatistical tools, qPCR, and IHC staining experiments were utilized to analyze data from The Cancer Genome Atlas (TCGA) and collected HCC tumor tissues. Single-cell RNA sequencing (scRNA-seq) analyses and a co-culture model of HCC cells with macrophages were performed to validate the findings from the biostatistical analyses. Results: Through the intersection of differentially expressed genes (DEGs), metabolism-related genes (MRGs), and co-expression genes (CEGs) with MICA in HCC, the EHHADH gene was identified. Gene set enrichment analyses were conducted to further confirm the role of EHHADH. EHHADH expression is decreased in HCC tumors and can serve as a prognostic biomarker for HCC. Expressions of MICA and EHHADH exhibited significant correlations with various phenotypic macrophages and exerted opposing effects on M1-like and M2-like macrophages infiltrating HCC. The underlying metabolic and molecular mechanisms revealed that MICA in tumor cells induced M2-like polarization through the PPAR/EHHADH pathway, which regulates the fatty acid oxidation (FAO) in macrophages. Conclusions: The metabolic gene EHHADH, which is associated with MICA, led to alterations in M2-like macrophages by promoting heightened fatty acid uptake and augmenting levels of FAO within macrophages. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease linked to fibrosis and hepatocellular carcinoma (HCC). Gut-derived lipopolysaccharide (LPS) promotes hepatic inflammation, fibrosis, and angiogenesis through toll-like receptor 4 (TLR4) signaling. This study examined the effects of rifaximin, a non-absorbable, gut-targeted antibiotic, on MASH-related liver fibrosis and early hepatocarcinogenesis, with a focus on the LPS–epiregulin–IL-8–angiogenesis axis.MASH was induced in Fischer 344 rats using a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD). Rifaximin (30 mg/kg/day) was orally administered for 12 weeks. Liver histology, gene expression, intestinal permeability, LPS levels, and angiogenic markers were evaluated. Rifaximin reduced hepatic inflammation, fibrosis, hydroxyproline content, and fibrogenic gene expression. The number and size of GST-P-positive preneoplastic lesions and proliferation-related genes were decreased. Portal LPS levels and Kupffer cell activation declined, with downregulation of Lbp, Cd14, Tlr4, and inflammatory cytokines. Rifaximin decreased hepatic epiregulin and IL-8 expression, attenuated CD34-positive neovascularization, and suppressed proangiogenic gene expression, accompanied by improved intestinal barrier function and reduced gut permeability. Rifaximin mitigates MASH progression by restoring gut barrier integrity, limiting LPS translocation, and inhibiting fibrogenic and angiogenic pathways. These results suggest its potential as a chemopreventive agent in MASH-related hepatocarcinogenesis. 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

Hepatocellular carcinoma (HCC) remains a major clinical challenge due to its high recurrence rate and limited response to monotherapies, such as sorafenib—the standard first-line therapy for advanced HCC. This is partly attributed to its cellular heterogeneity. Increasing evidence implies SRC family kinase (SFK) activation in HCC progression, highlighting the potential of SRC-targeted therapies. In this study, we observed that SRC and YES1 were significantly upregulated in clinical HCC specimens compared to its adjacent non-tumoral tissues (p < 0.001), suggesting relevance as therapeutic targets. High SRC expression was noticed in patients with poor prognosis, as confirmed in TCGA cohort. To evaluate the efficacy of dual targeting, we assessed the combination between SRC inhibitors, saracatinib and dasatinib, with sorafenib in six hepatic cell models, representing both S1 and S2 subtypes. Cytotoxicity assays demonstrated reduced cell viability with the combination therapies compared to either monotherapy, irrespective of the HCC subtype. Wound healing and Transwell migration assays revealed inhibition of cell migration and invasion following combination treatment, underscoring its potential to suppress metastatic behavior. RT-qPCR analysis further confirmed downregulation of the expression of MMP2 and MMP9, genes associated with HCC cell invasion. Additionally, combined therapies decreased VEGFA and HIF1A expression compared to sorafenib alone, suggesting a potential to counteract the adaptive resistance mechanisms of cells to sorafenib. In summary, the combination of SFK inhibitors with sorafenib significantly enhances anti-tumor activity, offering a promising strategy to address HCC cellular heterogeneity and improve treatment efficacy. Full article

Background: The N⁶-methyladenosine (m⁶A) modification of eukaryotic mRNA is the most prevalent of such epigenetic modifications and has recently been identified as a potential player in the pathogenesis and progression of hepatocellular carcinoma (HCC). With the increasing emergence of immunotherapy in the treatment of HCC, we have evaluated the potential of m⁶A-related genes in predicting overall survival and the therapeutic efficacy of immunotherapy in HCC patients. Methods: We employed transcriptomic data from TCGA-LIHC and GSE76427, comprising a total of 485 HCC patients, as the training set. Based on 23 recognized m⁶A regulators, we performed clustering analysis on HCC patients. The intersecting differentially expressed genes (DEGs) among subtypes were used in least absolute shrinkage and selection operator (LASSO) Cox and multivariate Cox regression analyses to construct the risk model. For the quantification of a risk model of HCC patients, a risk score was developed and correlated with clinical and immunological parameters. Furthermore, a single-cell transcriptomic atlas was used to analyze the relationship between model genes and immune cell subpopulations. Mechanistic studies included in vitro assays to validate the association between the m⁶A-related gene ANLN and the progression of HCC. Results: Internal (TCGA and GEO) and external validation (ICGC) suggested that an 8-gene risk score provides an accurate and stable prognostic assessment for HCC. Furthermore, the high-risk score, characterized by elevated TP53 mutation frequency, tumor mutation burden (TMB), and tumor stem cell characteristics indicated a poor prognosis. The prognostic signature was associated with immune cell infiltration in HCC. Those patients with a high-risk score had lower immune tolerance with a better prediction of the efficacy of immunotherapy. The risk model helps to assess and predict the response and prognosis of HCC patients to immune checkpoint inhibitors (ICIs). Additionally, single-cell RNA sequencing data revealed that the high-risk group had a higher proportion of T cells and fewer immunosuppressive T cells, potentially correlating with a better response to immunotherapy. Finally, in vitro experiments showed that ANLN, an m⁶A-related gene, promoted the proliferation and migration of HCC cells. Conclusions: In this study, we identified and validated an m⁶A gene signature consisting of eight genes that can be used to predict prognosis and immunotherapy efficacy in HCC patients. Full article

Background: Human proteins exist in numerous modifications—proteoforms—which are promising targets for biomarker studies. In this study, we aimed to generate comparative proteomics data, including proteoform patterns, from hepatocellular carcinoma (HCC) and nonmalignant liver tissues. Methods: To investigate protein profiles and proteoform patterns, we employed a panoramic, integrative top-down proteomics approach: two-dimensional gel electrophoresis (2DE) coupled with liquid chromatography–electrospray ionization–tandem mass spectrometry (LC-ESI-MS/MS). Results: We visualized over 2500 proteoform patterns per sample type, enabling the identification of distinct protein signatures and common patterns differentiating nonmalignant and malignant liver cells. Among these, 1270 protein patterns were uniformly observed across all samples. Additionally, 38 proteins—including pyruvate kinase PKM (KPYM), annexin A2 (ANXA2), and others—exhibited pronounced differences in proteoform patterns between nonmalignant and malignant tissues. Conclusions: Most proteoform patterns of the same protein were highly similar, with the dominant peak corresponding to theoretical (unmodified) protein parameters. However, certain proteins displayed altered proteoform patterns and additional proteoforms in cancer compared to controls. These proteins were prioritized for further characterization. Full article