As one of the most common and heterogeneous liver malignancies, hepatocellular carcinoma (HCC) remains a significant clinical challenge due to the lack of biomarkers for early diagnosis, challenges in accurate subtyping, and limitations of current therapeutic strategies with poor efficacy. Herein, based on DNA hairpin probes and dual-ligand zirconium (Zr)-based metal-organic frameworks (DMOFs), the multifunctional nanohybrids (DMOF@MnCO@CuS@Hairpin probe, DMCH) were developed to overcome these diagnostic and therapeutic obstacles. Two improved DNA molecular beacons and APE1 enzyme within HCC cells were utilized for sensitive miRNA imaging in vivo with high accuracy to differentiate HCC subtypes precisely. Furthermore, this "all-in-one" theranostic platform not only facilitates the generation of active oxygen species and conversion of near-infrared light into heat, but also releases carbon monoxide to inhibit the expression of HSP70 protein to improve photothermal (PTT) therapy efficiency during laser radiation, which enables PTT, photodynamic (PDT), chemodynamic (CDT), and gas therapy (GAT) for HCC treatment simultaneously. The developed nano-theranostics platform provides a novel way for efficient early screening, diagnosis, and intervention of HCC, and paves the path for future "bench-to-bedside" design of theranostics.

Hepatocellular carcinoma (HCC) is a serious global health threat associated with high morbidity and mortality. The importance of long non-coding RNAs (lncRNAs) in tumor progression is growing. The aim of this study was to explore the expression, functional properties and molecular mechanisms of LINC00504 in HCC.

Tumor tissue samples from HCC patients were collected to analyze the expression of LINC00504, miR-545-3p, and ARIH1 mRNA using RT-qPCR, and compared with various HCC cell lines (PLC/PRF/5, SNU-182, Hep3B, HuH-7) and a human normal liver epithelial cell line (THLE-2). Cell proliferation, apoptosis, and invasion were assessed using transfection vectors, CCK8 assay, flow cytometry, and Transwell. Interactions among LINC00504, miR-545-3p, and ARIH1 were confirmed through database predictions and luciferase reporter gene assays.

LINC00504 was underexpressed in HCC tissues and cell lines. Upregulation of LINC00504 inhibited cell proliferation, induced apoptosis, increased Bax and Caspase-3, decreased Bcl-2 mRNA, and suppressed invasion. miR-545-3p was overexpressed in HCC cells and was negatively regulated by LINC00504. Overexpression of miR-545-3p counteracted the effects of LINC00504 upregulation. ARIH1 was underexpressed in HCC tissues and had a negative correlation with miR-545-3p. miR-545-3p negatively regulated ARIH1 expression, and ARIH1 overexpression overturned the promotional effects of miR-545-3p on HCC cells.

This study uncovers the significant tumor-suppressing role of LINC00504 in HCC, potentially through a mechanism involving the targeting of miR-545-3p, which in turn inhibits the ARIH1. These findings offer new potential targets for HCC molecular treatment.

Hepatitis B virus (HBV)-related liver cancer is the third most common cause of cancer-related death globally. Hepatocyte remodeling, also known as hepatocyte transformation and immortalization, and hepatocellular carcinoma (HCC), are brought on by persistent inflammation caused by HBV in the host hepatocytes. One of the main concerns in the perspective of HBV-induced hepatocyte remodeling and liver cancer is accurately identifying cancer stages to maximize early screening and detection. Biological signatures have a significant impact on solving this problem.

This review article aimed to discuss the novel serum protein biomarkers for HBV-induced hepatocyte remodeling and HCC.

The information was collected from various peer-reviewed journals through electronic searches utilizing various search engines, including PubMed, Google Scholar, HINARI, and Cochrane Library from 2017 to 2024. Keywords for searches included "serum protein biomarkers in HBV-HCC," "blood-based biomarkers in HBV-HCC," and "viral biomarkers for HBV-HCC."

Recently, novel protein signatures have been discovered for the early diagnosis, treatment, and prognosis of HBV-induced hepatic cell remodeling and HCC from proteomic data sets. We have discussed the recent literature on the clinical utility of the protein signatures for the diagnosis and forecasting of HBV-associated hepatocyte remodeling and HCC, including golgi protein 73 (GP73), glypican-3 (GPC3), midkine (MDK), des-γ-carboxy-prothrombin (DCP), von Willebrand factor (vWF), pentraxin 3 (PTX3), pseudouridine synthases 7 (PUSs 7), squamous cell carcinoma antigen (SCCA), and osteopontin (OPN).

All these protein markers also exhibit the survival of HBV-related HCC patients, the proliferation, migration, antiapoptosis, mitogenesis, transformation, and angiogenesis of HBV-infected hepatocytes.

In this article, we commented on the work done by Jiang et al, where they synthesized a kakkatin derivative, 6-(hept-6-yn-1-yloxy)-3-(4-hydroxyphenyl)-7-methoxy-4H-chromen-4-one (HK), and investigated its antitumor activities and mechanism in gastric cancer MGC803 and hepatocellular carcinoma (HCC) SMMC-7721 cells. HK was evaluated for its antitumor activity as compared to kakkatin and cisplatin. This article focused on various risk factors of HCC, the mechanism of HCC progression and molecular targets of the kakkatin derivative, and limitations of available treatment options. HCC is a predominant form of primary liver cancer characterized by the accumulation of multiple gene modifications, overexpression of protooncogenes, altered immune microenvironment, and infiltration by immune cells. Puerariae flos (PF) has been used in traditional medicine in China, Korea, and Japan for lung clearing, spleen awakening, and relieving alcohol hangovers. PF exerts antitumor activity by inhibiting cancer cell proliferation, invasion, and migration. PF induces apoptosis in alcoholic HCC via the estrogen-receptor 1-extracellular signal-regulated kinases 1/2 signaling pathway. Kakkatin isolated from PF is known as a hepatoprotective bioflavonoid. The kakkatin derivative, HK, exhibited anticancer activity against HCC cell lines by inhibiting cell proliferation and upregulating nuclear factor kappa B subunit 1 and phosphodiesterase 3B. However, further preclinical and clinical studies are required to establish its therapeutic potential against HCC.

Evaluating portal hypertension is crucial for patients with hepatocellular carcinoma (HCC) who are candidates for liver resection. Total bile acid (TBA) is an easily accessible marker, but its potential as a non-invasive indicator of portal hypertension in patients with HCC is yet to be fully established.

This study included patients with HCC classified as Child-Pugh stage A who underwent liver resection at a referral hospital. Elevated TBA levels were defined as serum TBA >10 μmol/L, while normal levels were ≤10 μmol/L.

A total of 167 patients with HCC with Child-Pugh Class A who underwent liver resection were analyzed. The cohort was divided into normal (n = 125) and elevated TBA groups (n = 42). Compared to patients with normal TBA levels, those with elevated TBA had significantly higher 15-min indocyanine green retention rates (ICG R15) (p <0.001), higher Child-Pugh scores (p <0.001), more advanced Laennec fibrosis stages (p = 0.039), and a higher incidence of esophageal gastric varices (p = 0.001) and post-hepatectomy liver failure (p = 0.001). Multivariate analysis showed that elevated TBA was independently associated with ICG R15 (odds ratio [OR] = 1.150, 95% confidence interval [CI] = 1.055-1.254, p = 0.002), fibrosis stages (OR = 1.973, 95% CI = 1.026-3.796, p = 0.042), and Child-Pugh score (OR = 4.121, 95% CI = 1.367-12.424, p = 0.012).

Elevated TBA levels in patients with HCC with Child-Pugh class A are significantly associated with portal hypertension and a higher incidence of post-hepatectomy liver failure.

Liver cancer, specifically hepatocellular carcinoma (HCC), stands out as one of the most formidable solid tumors, characterized by a dauntingly low survival rate. At the forefront of the tumor microenvironment (TME) orchestrating the initiation and advancement of HCC are cancer-associated fibroblasts (CAFs). TGF-β, widely recognized as a potent activator of CAFs, not only regulates their activity but also assumes a pivotal role in the metastatic journey of the tumor. In our recent study, drawing from the GEO database, we identified two fibroblast subtypes in HCC through single-cell RNA sequencing (scRNA-seq) and explore the expression and distribution of TGF-β and its receptors in the TME of HCC. Subsequently, we investigated the interactions between tumor cells expressing high levels (TGFB1high) and low levels (TGFB1low) of TGF-β in the HCC TME and the two subtypes of CAFs. We also employed multi-color immunohistochemistry (mIHC) technology to examine the expressions of FAP, α-SMA, CD4, Foxp3, and TGF-β in HCC tissues within a tissue microarray. Additionally, we analyzed clinical associations, prognostic values, and the correlation of these molecules. These insights advance our understanding of the molecular mechanisms driving HCC progression and underscore the intricate interplay between tumor cells and the stromal components of the TME.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and, with only 15-20% of HCC patients being suitable for potentially curative treatments, the vast majority of patients with HCC ultimately require systemic therapy. For decades, the choice of effective systemic therapy for HCC remained sparse. In recent years, after the combination of atezolizumab and bevacizumab demonstrated superior overall survival over the first-line standard, sorafenib, there has been a major therapeutic paradigm shift to immunotherapy-based regimens for HCC. While representing a great leap forward for the treatment of this cancer, the reality is that less than one-third of patients achieve an objective response to immune checkpoint inhibitor-based therapy, so there remains a significant clinical need for further therapeutic optimization. In this review, we provide an overview of the current landscape of immunotherapy for unresectable HCC and delve into the tumor intrinsic and extrinsic mechanisms of resistance to established immunotherapies with a focus on novel therapeutic targets with strong translational potential. Following this, we spotlight emerging immunotherapy approaches and notable clinical trials aiming to optimize immunotherapy efficacy in HCC that include novel immune checkpoint inhibitors, tumor microenvironment modulators, targeted delivery systems, and locoregional interventions.

The emerged apoptosis/ferroptosis synergistic platinum-based therapy has attracted a lot of attention but is far from clinic use due to high systemic toxicity. Herein, a series of novel precise carrier-free self-assembled platinum(IV) nanoparticles with lipid regulation effect named FSPNPs (5NPs-8NPs) were constructed via connecting fenofibrate acid (FA) to cisplatin or oxaliplatin-derived platinum(IV)-intermediates with disulfide bonds. FSPNPs can be stimulated by high-glutathione/ascorbic acid and acidity environment to produce an "explosion-like" cascade release process. Cell-activity showed precision of FSPNPs, which accumulated more in tumor cells and inhibited cell proliferation. Especially, 5NPs have higher cell selectivity than cisplatin. FSPNPs downregulated glutathione/glutathione peroxidase 4, increased reactive oxygen species/lipid peroxidation/malondialdehyde, induced DNA damage/S-phase arrest, and regulated p53/Bcl-2/Bax to trigger the apoptosis/ferroptosis hybrid pathway. The released FA and derivates were docked into the peroxisome proliferator-activated receptor α with activating cholesterol metabolism to destroy membrane integrity. FSPNPs also showed good biocompatibility and superior antitumor activity with no observable tissue damage.

Hepatocellular carcinoma (HCC), one of the most prevalent malignant tumors causing the highest mortality globally, imposes an especially heavy burden of disease in China. Individuals living in high-altitude areas have a lower incidence of and mortality resulting from HCC compared with those in low-altitude regions do, potentially due to adaptive evolution in responses to hypoxic stress. Notably, high-altitude hypoxic stress is associated with the development and progression of HCC. Hypoxic stress may be involved in the development and progression of HCC by modulating the senescence, apoptosis, metabolism, tumor microenvironment, and tumor immunity of HCC cells. Additionally, the latest clinical findings indicate that high-altitude hypoxic environment has a significant impact on liver regeneration after HCC resection surgery. However, there is still a debate going on regarding whether high-altitude hypoxic stress promotes or inhibits the progression of HCC. This review covers three main aspects, the impact of adaptive evolution to high-altitude hypoxic stress on the development and progression of HCC in long-term residents of high-altitude areas, the effects of high-altitude hypoxic stress on the senescence, apoptosis, metabolism, tumor microenvironment, tumor metabolism, and tumor immunity of HCC cells, and the effect of high-altitude hypoxic stress on liver regeneration after HCC resection. We discussed the effect of changes in oxygen concentrations, cellular context, and tissue microenvironment on HCC development and progression. Moreover, we highlighted the potential for using research findings on mechanisms underlying high-altitude hypoxic stress to optimize HCC treatment strategies.

Liver fibrosis is a pathological response to liver damage induced by multiple etiologies including NASH and CCl4, which may further lead to cirrhosis and hepatocellular carcinoma (HCC). Despite the increasing understanding of liver fibrosis and HCC, clinical prognosis and targeted therapy remain challenging.

This study integrated single-cell sequencing analysis, bulk sequencing analysis, and mouse models to identify highly expressed genes, cell subsets, and signaling pathways associated with liver fibrosis and HCC. Clinical prediction models and prognostic genes were established and verified through machine learning, survival analysis, as well as the utilization of clinical data and tissue samples from HCC patients. The expression heterogeneity of the core prognostic gene, along with its correlation with the tumor microenvironment and prognostic outcomes, was analyzed through single-cell analysis and immune infiltration analysis. In addition, the cAMP database and molecular docking techniques were employed to screen potential small molecule drugs for the treatment of liver fibrosis and HCC.

We identified 40 pathogenic genes, 15 critical cell subsets (especially Macrophages), and regulatory signaling pathways related to cell adhesion and the actin cytoskeleton that promote the development of liver fibrosis and HCC. In addition, 7 specific prognostic genes (CCR7, COL3A1, FMNL2, HP, PFN1, SPP1 and TENM4) were identified and evaluated, and expression heterogeneity of core gene SPP1 and its positive correlation with immune infiltration and prognostic development were interpreted. Moreover, 6 potential small molecule drugs for the treatment of liver fibrosis and HCC were provided.

The comprehensive investigation, based on a bioinformatics and mouse model strategy, may identify pathogenic genes, cell subsets, regulatory mechanisms, prognostic genes, and potential small molecule drugs, thereby providing valuable insights into the clinical prognosis and targeted treatment of liver fibrosis and HCC.

Intra-tumor immune infiltration plays a pivotal role in the interaction with tumor cells in hepatocellular carcinoma (HCC). However, its phenotype and related spatial structure remained elusive. To address these limitations, we conducted a comprehensive study combining spatial data (38,191 spots from eight samples) and single-cell data (56,022 cells from 20 samples). Our analysis revealed two distinct infiltration patterns: immune exclusion and immune activation. Plasma cells emerged as the primary cell type within intra-tumor immune clusters. Notably, we observed the co-location of CCL19+ fibroblasts with plasma cells, which secrete chemokines and promote T-cell activation and leukocyte migration. Conversely, in immune-exclusion samples, this co-location was primarily observed in the adjacent normal area. This co-localization correlated with T cell infiltration and the formation of tertiary lymphoid structures, validated by multiplex immunofluorescence conducted on twenty HCC samples. Both CCL19+ fibroblasts and plasma cells were associated with favorable survival outcomes. In an immunotherapy cohort, HCC patients who responded favorably exhibited higher infiltration of CCL19+ fibroblasts and plasma cells. Additionally, we observed the accumulation of DKK1+ tumor cells within the tumor area in immune-exclusion samples, particularly at the tumor boundary, which inhibited the infiltration of CCL19+ fibroblasts and plasma cells into the tumor area. Furthermore, in immune-exclusion samples, the SPP1 signaling pathway demonstrated the highest activity in communication between tumor and immune clusters, and CCL19-CCR7 played a pivotal role in the self-communication of immune clusters. This study elucidates immune exclusion and immune activation patterns in HCC and identifies relevant factors contributing to immune resistance.

Liver cancer is a highly lethal malignancy with frequent recurrence, widespread metastasis, and low survival rates. The aim of this study was to explore the role of Endoglin (ENG) in liver cancer progression, as well as its impacts on angiogenesis, immune cell infiltration, and the therapeutic efficacy of sorafenib.

A comprehensive evaluation was conducted using online databases Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), 76 pairs of clinical specimens of tumor and adjacent non-tumor liver tissue, and tissue samples from 32 hepatocellular carcinoma (HCC) patients treated with sorafenib. ENG expression levels were evaluated using quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR), Western blot, and immunohistochemical analysis. Cox regression analysis, Spearman rank correlation analysis, and survival analysis were used to assess the results. Functional experiments included Transwell migration assays and tube formation assays with Human Umbilical Vein Endothelial Cells (HUVECs).

Tumor cells exhibited retro-differentiation into endothelial-like cells, with a significant increase in ENG expression in these tumor-derived endothelial cells (TDECs). High expression of ENG was associated with more aggressive cancer characteristics and worse patient prognosis. Pathway enrichment and functional analyses identified ENG as a key regulator of immune responses and angiogenesis in liver cancer. Further studies confirmed that ENG increases the expression of Collagen type Iα1 (COL1A1), thereby promoting angiogenesis in liver cancer. Additionally, HCC patients with elevated ENG levels responded well to sorafenib treatment.

This study found that ENG is an important biomarker of prognosis in liver cancer. Moreover, ENG is associated with endothelial cell differentiation in liver cancer and plays a crucial role in formation of the tumor vasculature. The assessment of ENG expression could be a promising strategy to identify liver cancer patients who might benefit from targeted immunotherapies.

An increasing number of studies have shown that the consumption of soybeans and soybeans products is beneficial to human health, and the biological activity of soy products may be attributed to the presence of Soy Isoflavones (SI) in soybeans. In the intestinal tracts of humans and animals, certain specific bacteria can metabolize soy isoflavones into equol. Equol has a similar chemical structure to endogenous estradiol in the human body, which can bind with estrogen receptors and exert weak estrogen effects. Therefore, equol plays an important role in the occurrence and development of a variety of hormone-dependent malignancies such as breast cancer and prostate cancer. Despite the numerous health benefits of equol for humans, only 30-50% of the population can metabolize soy isoflavones into equol, with individual variation in gut microbiota being the main reason. This article provides an overview of the relevant gut microbiota involved in the synthesis of equol and its anti-tumor effects in various types of cancer. It also summarizes the molecular mechanisms underlying its anti-tumor properties, aiming to provide a more reliable theoretical basis for the rational utilization of equol in the field of cancer treatment.

Despite advances in cancer treatment, hepatocellular carcinoma (HCC), the most common form of liver cancer, remains a major public health problem worldwide. The immune microenvironment plays a critical role in regulating tumor progression and resistance to therapy, and in HCC, the tumor microenvironment (TME) is characterized by an abundance of immunosuppressive cells and signals that facilitate immune evasion and metastasis. Recently, anti-cancer immunotherapies, therapeutic interventions designed to modulate the immune system to recognize and eliminate cancer, have become an important cornerstone of cancer therapy. Immunotherapy has demonstrated the ability to improve survival and provide durable cancer control in certain groups of HCC patients, while reducing adverse side effects. These findings represent a significant step toward improving cancer treatment outcomes. As demonstrated in clinical trials, the administration of immune checkpoint inhibitors (ICIs), particularly in combination with anti-angiogenic agents and tyrosine kinase inhibitors, has prolonged survival in a subset of patients with HCC, providing an alternative for patients who progress on first-line therapy. In this review, we aimed to provide an overview of HCC and the role of the immune system in its development, and to summarize the findings of clinical trials involving ICIs, either as monotherapies or in combination with other agents in the treatment of the disease. Challenges and considerations regarding the administration of ICIs in the treatment of HCC are also outlined.

Plumbagin (PL) has been shown to effe ctively inhibit autophagy, suppressing invasion and migration of hepatocellular carcinoma (HCC) cells. However, the specific mechanism remains unclear. This study aimed to investigate the effect of PL on tumor growth factor (TGF)-β-induced epithelial-mesenchymal transition (EMT) in HCC.

Huh-7 cells were cultured, and in vivo models of EMT and HCC-associated lung metastasis were developed through tail vein and in situ injections of tumor cells. In vivo imaging and hematoxylin and eosin staining were used to evaluate HCC modeling and lung metastasis. After PL intervention, the expression levels of Snail, vimentin, E-cadherin, and N-cadherin in the liver were evaluated through immunohistochemistry and Western blot. An in vitro TGF-β-induced cell EMT model was used to detect Snail, vimentin, E-cadherin, and N-cadherin mRNA levels through a polymerase chain reaction. Their protein levels were detected by immunofluorescence staining and Western blot.

In vivo experiments demonstrated that PL significantly reduced the expression of Snail, vimentin, and N-cadherin, while increasing the expression of E-cadherin at the protein levels, effectively inhibiting HCC and lung metastasis. In vitro experiments confirmed that PL up-regulated epithelial cell markers, down-regulated mesenchymal cell markers, and inhibited EMT levels in HCC cells.

PL inhibits Snail expression, up-regulates E-cadherin expression, and down-regulates N-cadherin and vimentin expression, preventing EMT in HCC cells and reducing lung metastasis.

Liver cancer is the third leading of tumor death, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immune checkpoint inhibitors (ICIs) are yielding much for sufferers to hope for patients, but only some patients with advanced liver tumor respond. Recent research showed that tumor microenvironment (TME) is critical for the effectiveness of ICIs in advanced liver tumor. Meanwhile, metabolic reprogramming of liver tumor leads to immunosuppression in TME. These suggest that regulating the abnormal metabolism of liver tumor cells and firing up TME to turn "cold tumor" into "hot tumor" are potential strategies to improve the therapeutic effect of ICIs in liver tumor. Previous studies have found that YAP1 is a potential target to improve the efficacy of anti-PD-1 in HCC. Here, we review that YAP1 promotes immunosuppression of TME, mainly due to the overstimulation of cytokines in TME by YAP1. Subsequently, we studied the effects of YAP1 on metabolic reprogramming in liver tumor cells, including glycolysis, gluconeogenesis, lipid metabolism, arachidonic acid metabolism, and amino acid metabolism. Lastly, we summarized the existing drugs targeting YAP1 in the treatment of liver tumor, including some medicines from natural sources, which have the potential to improve the efficacy of ICIs in the treatment of liver tumor. This review contributed to the application of targeted YAP1 for combined therapy with ICIs in liver tumor patients.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. Due to the insidious onset and rapid progression and a lack of effective treatments, the prognosis of patients with HCC is extremely poor, with the average 5-year survival rate being less than 10%. The tumor microenvironment (TME), the internal environment in which HCC develops, can regulate the oncogenesis, development, invasion, and metastasis of HCC. During the process of cancer progression, HCC cells can regulate the biological behaviors of tumor cells, cancer-associated fibroblasts, cancer-associated immune cells, and other cells in the TME by releasing exosomes containing specific signals, thereby promoting cancer progression. However, the exact molecular mechanisms and the roles of exosomes in the specific cellular regulation of these processes are not fully understood. Herein, we summarized the TME components of HCC, the sources and the biological traits of exosomes in the TME, and the impact of mechanical factors on exosomes. In addition, special attention was given to the discussion of the effects of HCC-exosomes on different types of cells in the microenvironment. There are still many difficulties to be overcome before exosomes can be applied as carriers in clinical cancer treatment. First of all, the homogeneity of exosomes is difficult to ensure. Secondly, exosomes are mainly administered through subcutaneous injection. Although this method is simple and easy to implement, the absorption efficiency is not ideal. Thirdly, exosome extraction methods are limited in number and inefficient, making it difficult to prepare exosomes in large quantities. It is important to ensure that exosomes are used in sufficient quantities to trigger an effective tumor immune response, especially for exosome-mediated tumor immunotherapy. With the improvement in identification, isolation, and purification technology, exosomes are expected to be successfully used in the clinical diagnosis of early-stage HCC and the clinical treatment of liver cancer.