The lipopeptides produced by Bacillus subtilis have anti-cancer potential. We had previously identified a secondary metabolite of B. subtilis strain Z15 (BS-Z15), which has an operon that regulates lipopeptide synthesis, and also demonstrated that the fermentation products of this strain exerted antioxidant and pro-immune effects. The purpose of this study was to investigate in vitro and in vivo the anticancer effects of BS-Z15 secondary metabolites (BS-Z15 SMs) on hepatocellular carcinoma (HCC) cells. BS-Z15 SMs significantly inhibited H22 cell-derived murine xenograft tumor growth without any systemic toxicity. In addition, BS-Z15 SMs decreased the viability of H22 cells and BEL-7404 cells in vitro with respective IC50 values of 33.83 and 27.26 µg/mL. Consistent with this, BS-Z15 SMs induced apoptosis and G0/G1 phase arrest in the BEL-7404 cells, and the mitochondrial membrane potential was also significantly reduced in a dose-dependent manner. Mechanistically, BS-Z15 SMs upregulated the pro-apoptotic p53, Bax, cytochrome C, and cleaved-caspase-3/9 proteins and downregulated the anti-apoptotic Bcl-2. These findings suggest that the induction of apoptosis in HCC cells by BS-Z15 SMs may be related to the mitochondrial pathway. Thus, the secondary metabolites of B. subtilis strain Z15 are promising to become new anti-cancer drugs for the clinical treatment of liver cancer.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide and a major cause of death in cirrhosis. The prognosis of HCC is poor, with a mortality rate close to the morbidity rate. Once HCC develops distant metastasis, the area affected by the cancer cells is significantly enlarged, and there is still no effective treatment for HCC. Therefore, the development of effective drugs is essential to improve the survival rate of HCC patients. We designed and optimised a delivery system for compound 1, derived from camptothecin extract, by developing a multifunctional fluorescent drug delivery platform composed of polylactic acid (PLA), chitosan (CS), and fluorescein isothiocyanate (FITC) (PLA-CS-FITC). This system successfully encapsulated CP1 and compound 1, forming a PLA-CS-FITC@CP1@1 composite nanocarrier with dual functions for drug delivery and real-time fluorescence monitoring. The effects of the system on HCC proliferation and its regulation were evaluated by treating HCC cells in vitro, which provided an experimental basis for the development of drugs for HCC.

Exploring the mechanisms underlying sorafenib resistance that arises in hepatocellular carcinoma (HCC) may provide new treatment perspectives.

Drug-resistant and drug-sensitive HCC cell lines were constructed from existing HepG2 and Huh7 cell lines, and gene expression profiles were determined. Genes differentially expressed between the resistant and sensitive lines were identified and organized into modules based on weighted gene co-expression network analysis. Pathways and biological processes involving the module genes were explored and validated using gene set enrichment analysis. By analyzing the expression differences of Long non-coding ribonucleic acid (RNAs), microRNAs (miR), circular RNAs, and messenger RNAs between drug-resistant and sensitive cell lines, a gene regulatory network was constructed to reveal the mechanism of sorafenib resistance. In addition, we also analyzed the correlation between the candidate sorafenib resistance gene and the survival of patients with liver cancer.

Our analyses suggested that sorafenib resistance could arise when the circular RNA circ_SPECC1 regulated the microRNA hsa-let-7c-5p, which in turn regulated the cell cycle proteins cyclin-dependent kinase 1 and polo-like kinase 1, as well as interleukin 13 receptor, alpha 1 in the Janus kinase-signal transducer (JAK-STAT) and activator of transcription signaling pathway. Patient survival was associated with miR-18a-z and mitogen-activated protein kinase kinase 4 levels.

Sorafenib resistance in HCC may involve the circ_SPECC1, hsa-let-7c-5p, cell cycle, and JAK-STAT signaling pathways. These insights may guide future efforts to mitigate or prevent such resistance.

RNA m6 methyladenosine (m6A) modifications impact tumor biology and immune processes, particularly in hepatocellular malignant tumors. Using a consensus clustering algorithm on 371 hepatocellular carcinoma (HCC) samples, we identified three m6A-modified subtypes and correlated them with positive tumor microenvironment (TME) markers for distinct immune phenotypes. Stratifying patients based on m6A scores revealed a low presentation group with better immune penetration, lower tumor mutation load, and increased expression of immune checkpoint markers like CTLA-4 and PD-1, suggesting enhanced responsiveness to immunization therapy. A machine-learning model of 23 m6A genes was constructed. Single-cell analysis revealed a surprising enrichment of IGFBP3 in astrocytes, prompting the exploration of associated signaling pathways. Experimental verification shows that IGFBP3 is significantly enhanced in normal tissues, while immunohistochemical analysis shows that its expression is lower in tumor tissues, indicating its protective effect in HCC and a good prognosis. Importantly, high IGFBP3 expression is associated with better outcomes in patients receiving immunotherapy. Moreover, cytotoxic T lymphocyte (CTL) experiments have confirmed that high expression of IGFBP3 is associated with stronger T cell-killing ability. In summary, the comprehensive evaluation of m6A modification, immune characteristics, and single-cell analysis in this study not only revealed the TME of HCC but also made significant contributions to the progress of personalized HCC immunotherapy targeting IGFBP3. This study provides a solid theoretical foundation for clinical translation and emphasizes its potential impact on developing effective treatment strategies.

Abnormal expression of Fanconi anaemia complementation group I (FANCI) has been implicated in carcinogenesis. However, the precise role of FANCI in the development of hepatocellular carcinoma (HCC) remains unclear.

We conducted a comprehensive bioinformatics analysis of FANCI's role based on HCC patient sequencing data in the TCGA and GEO databases. Then, we performed qPCR, Western blotting (WB), and immunohistochemistry (IHC) assays. SiRNA-mediated knockdown of FANCI was conducted, followed by CCK-8, EdU staining, and colony formation experiments to evaluate the impact of FANCI knockdown on HCC cell behaviour. Flow cytometry was employed to explore alterations in the cell cycle after FANCI knockdown in HCC cell lines. Furthermore, RNA sequencing was performed to investigate potential mechanisms following FANCI knockdown, and WB analysis was used to validate the corresponding pathway.

Our bioinformatics analysis revealed elevated expression of FANCI in HCC, which was subsequently validated through qPCR, WB, and IHC assays. High expression of FANCI was significantly associated with a poor prognosis in HCC patients. Univariate and multivariate Cox regression analyses identified FANCI as an independent prognostic risk factor for HCC patients. Additionally, the coexpressed genes of FANCI were found to be associated with multiple cancer pathways. Knockdown of FANCI expression significantly inhibited HCC cell proliferation and colony formation by inducing cell cycle arrest. Further WB analysis revealed that FANCI knockdown suppressed the expression of Cyclin D1 and p-AKT while increasing the expression of GSK-3β in HCC cells. However, no significant differences were observed in the expression levels of AKT and PI3K.

Overall, our research provides substantial proof of FANCI's crucial function as an oncogene in HCC. It could serve as a potential prognostic marker, therapeutic target, and tumorigenic factor in HCC.

Background/Objectives: The issue of HCC recurrence in patients with liver cirrhosis and chronic HCV infection after DAA treatment as well as the issue of de novo HCC in individuals with chronic HCV hepatitis treated with DAA is of great importance. In this review, the two important aspects are discussed and, finally, an algorithm for approaching the patient with HCC and chronic HCV infection is proposed. Methods: A literature search of the two databases (PubMed and Scopus) was conducted using the terms 'chronic hepatitis C' and/or 'liver cirrhosis' and 'hepatocellular carcinoma', from database inception to December 2024. Results: Thirty-one studies have examined the risk of HCC recurrence. Most of these studies conclude that DAA treatment reduces the risk of HCC recurrence compared to patients who did not receive DAA. There are considerable differences across various world regions. These variations may arise from: differences in genotypes, baseline characteristics of the populations, variability in DAA treatment protocols, and differences in follow-up intervals. Eleven studies that investigated the issue of de novo HCC after DAA were reviewed, of which two included historical cohorts of untreated patients. Conclusions: The conclusion is that these patients present a low or equal risk of HCC incidence compared to untreated patients, and the risk factors for HCC are: lower platelet number, impaired liver function, nonresponse to DAA. Most patients with chronic hepatitis C and HCC should receive DAAs, except for those in BCLC stage D, but we must emphasize that timing of intervention is crucial and it is very important to evaluate possible drug interactions.

Hepatocellular carcinoma (HCC) is the most common malignant tumor worldwide with a high mortality rate. Herein, this study aims to explore the molecular mechanisms of E2F transcription factor 1 (E2F1), ubiquitin specific peptidase 19 (USP19) and c-Myc in regulating HCC progression.

RT-qPCR and western blotting were utilized to assess mRNA and protein expression, respectively. The behavior of cells was examined through Methylthiazolyldiphenyl-tetrazolium bromide (MTT), flow cytometry, transwell, and cell sphere formation assays. Glycolysis-related indicators were detected by kits. The interaction between USP19 and c-Myc was measured by co-immunoprecipitation (Co-IP). Dual-luciferase reporter assay and Chromatin Immunoprecipitation (ChIP) assays were used to assess the binding of E2F1 and USP19 promoter. A mouse xenograft model was established for the purpose of analysis in vivo.

High level of c-Myc was observed in HCC tissues and cells. Silencing c-Myc results in the suppression of cell migration, invasion, proliferation, and glycolysis or promotion of apoptosis. USP19 directly bound to c-Myc, and maintained its stability by removing ubiquitination on c-Myc. Overexpression of c-Myc in HCC cells rescued the anti-tumor effect of USP19 deletion. E2F1 promoted USP19 transcription, and increased USP19 expression counteracts the effects of E2F1 depletion on cell behaviors. In vivo, USP19 knockdown controlled HCC growth by modulating c-Myc.

E2F1 activated USP19 transcription, thereby stabilizing c-Myc via deubiquitination and accelerating HCC progression.

High mobility group protein N2 (HMGN2) related pathways are involved in chromatin regulation/acetylation. It has been reported to be involved in several types of cancers. A recent sequencing study suggested that HMGN2 might be involved in the progression of hepatocellular carcinoma (HCC). This study aimed to explore the role of HMGN2 in HCC, which has been proven to be involved in the development of HCC. In this study, we collected clinical samples and cultured normal hepatocytes and hepatocellular carcinoma cell lines to detect HMGN2 expression levels using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and western blot assay. Subsequently, to determine the role of HMGN2 in HCC, HMGN2 was overexpressed in HCC cell lines. MTT (3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide) assay was used to detect the cell proliferative capacity, and proliferation-related proteins were detected by RT-qPCR and western blot assay. To observe the effect of HMGN2 on cell migration and invasion capacity, Transwell assay was performed. Then, cell apoptosis was detected by flow cytometry, and caspase3 and cleaved-caspase3 were detected using western blot assay. Finally, EMT (epithelial to mesenchymal transition)-related proteins, and matrix metalloproteinase-2 (MMP-2) and MMP-9 expression were detected by RT-qPCR and western blot assay. HMGN2 expression was decreased in HCC tissues as well as in HCC cell lines. After overexpression of HMGN2, MTT results suggested that cell proliferation was decreased, and flow cytometry results showed that the apoptosis level was increased and ki-67 and proliferating cell nuclear antigen (PCNA) expression levels were decreased. On the contrary, cleaved-caspase 3 expression level was increased. HCC cells overexpressing HMGN2 showed a drastic reduction in the number of migrating and invading cells, and the expression levels of MMP-2 and MMP-9 were significantly decreased. Finally, E-cadherin expression was elevated in HCC cells transfected with the HMGN2-plasmid, while N-cadherin showed the opposite result. HMGN2 expression was significantly decreased in patients with HCC. HMGN2 inhibits the malignant behavior of HCC cells and is a potential therapeutic target for HCC.

(1) Background and aim: Aloe arborescens Mill. ( A. arborescens ) is one of the most widely distributed species in the genus Aloe and has garnered widespread recognition for its anticancer properties. However, the molecular mechanisms underlying these activities have not yet been fully elucidated. This study aimed to explore the effects of the plant polar glycosidic fraction (AAG) on hepatocellular carcinoma (HCC) in an in vivo model induced by diethylnitrosamine (DEN). (2) Experimental procedure: The fraction was standardized using HPLC-PDA-MS/MS fingerprinting, and two distinct intragastric AAG dose regimens were examined (10 and 20 mg/kg) in combination with DEN 200 mg/kg. Serum alpha-fetoprotein (AFP), gamma-glutamyl transferase (γ-GGT), glutathione S-transferase placental (GST-P), mRNA expression of metabolic cytochrome enzymes (CYP1A3 and CYP2B2), inflammatory genes (nuclear factor kappa-B p65 subunit; NF-κB p65), metalloproteases 9 (MMP9), tissue inhibitors of metalloproteases (TIMP1), transforming growth factor beta 1 (TGFβ1), and histological features were assessed. (3) Key results and conclusions and implications: AAG was characterized by five major secondary metabolites: saponins, chromones, anthraquinone, and triterpenes. The fraction reduced hepatic malignancy characteristics by diminishing the size and number of altered foci and lowering hepatic cancer biomarkers, such as γ-GGT, AFP, and GST-positive foci. It also reduced the mRNA levels of CYP1A3 and CYP2B2, NF-κB p65, and MMP9, hepatic Ki-67, and TGFβ1 while upregulating TIMP1 levels. This study revealed that AAG exhibited a marked suppressive effect on HCC cell proliferation, displaying a range of mechanistic actions, including decreasing the metabolic activation of cytochrome enzymes, which consequently reduced the production of reactive oxygen species and other genes implicated in cancer development. AAG could be a significant therapeutic candidate for patients diagnosed with hepatocarcinoma.

The diagnostic performance of liquid biopsy-based biomarkers for HCC was comprehensively compared in this network meta-analysis (NMA).

A thorough literature search was conducted to identify all comparative studies from January 1, 2000, to January 11, 2024. The QUADAS-2 tool was utilized to appraise the quality of studies involving diagnostic performance. R (v4.3.3) and an ANOVA model-based NMA were used to assess the diagnostic accuracy of each biomarker.

This study included 82 studies comprising a total of 15,024 patients.CircRNA demonstrated significantly superior performance in distinguishing HCC from healthy populations (superiority index: 3.550 (95% CI [0.143-3])) compared to other diagnostic biomarkers for HCC. "mRNA exhibited significantly superior performance in distinguishing HCC from liver disease patients (superiority index:10.621 (95% CI [7-11])) compared to other diagnostic biomarkers for HCC. Further subgroup analysis of the top-ranking liquid biopsy-based diagnostic biomarkers revealed that hsa_circ_000224 (superiority index: 3.091 (95% CI[0.143-9]) ranked remarkably higher in distinguishing HCC from both healthy populations and liver disease patients. Subgroup analysis of mRNA demonstrated that KIAA0101 mRNA (superiority index: 2.434 (95% CI [0.2-5]) ranked remarkably higher in distinguishing HCC from healthy populations and liver disease patients, respectively.

The results of this meta-analysis show that circRNA and mRNA are the first choice for HCC diagnosis. Subsequent analysis of circRNA and mRNA highlighted hsa_circ_000224, hsa_circ_0003998, KIAA0101 mRNA and GPC-3mRNA as the optimal diagnostic biomarkers for distinguishing HCC from healthy populations and liver disease patients, respectively. Well-structured prospective studies are crucial to comprehensively validate these findings.

https://www.crd.york.ac.uk/PROSPERO/,identifier CRD42024521299.

Hepatocellular carcinoma (HCC) is a prevalent primary liver malignancy and a leading cause of cancer-related mortality worldwide. Despite advancements in therapeutic strategies, the 5-year survival rate for individuals undergoing curative resection remains between 10% and 15%. Consequently, identifying molecular targets that specifically inhibit the proliferation and metastasis of HCC cells is critical for improving treatment outcomes. Database analysis using Targetscan identified complementary binding sites for the human-specific miRNA hsa-miR-6894-3p (hereafter referred to as miR-6894-3p) on SHROOM2, and Starbase data suggested a potential regulatory interaction between lnc-MAP3K13-3:1 and miR-6894-3p in liver cancer.

This study aimed to investigate the role of lnc-MAP3K13-3:1 in regulating miR-6894-3p, with a focus on its impact on proliferation, apoptosis, migration, and related cellular processes in liver cancer cells via SHROOM2 regulation.

Quantitative PCR (qPCR) was initially employed to measure the expression levels of lnc-MAP3K13-3:1 and miR-6894-3p in three HCC cell lines: HepG2, HuH-7, and Li-7. Based on these initial assessments, two cell lines were selected for further experimentation. Stable cell lines overexpressing lnc-MAP3K13-3:1 were developed, and cells were transfected with miR-6894-3p mimics or a mimic negative control (NC). After 24 h, qPCR was utilized to quantify the relative expression of lnc-MAP3K13-3:1, miR-6894-3p, SHROOM2, and Caspase9 mRNA in each group. Cell proliferation was analyzed using the cell counting Kit-8 assay, while flow cytometry was used to assess cell cycle distribution and apoptosis. Migration capabilities were evaluated through cell scratch assays, and dual-luciferase assays were utilized to verify interactions between miR-6894-3p, lnc-MAP3K13-3:1, and SHROOM2.

Overexpression of lnc-MAP3K13-3:1 and miR-6894-3p mimic transfection resulted in increased expression of SHROOM2 and Caspase9 mRNA, as demonstrated by qPCR. The miR-6894-3p mimic regulated the activity of lnc-MAP3K13-3:1. Functional assays showed that lnc-MAP3K13-3:1 overexpression inhibited proliferation in HuH-7 and Li-7 cells, promoted apoptosis, reduced migration in Li-7 cells, but enhanced migration in HuH-7 cells. Additionally, lnc-MAP3K13-3:1 overexpression significantly increased the proportion of HuH-7 cells in the G2/M phase and Li-7 cells in the S phase. The miR-6894-3p mimic modulated the effects of lnc-MAP3K13-3:1 on cell proliferation, apoptosis, and migration. Dual-luciferase assays confirmed direct binding between lnc-MAP3K13-3:1 and miR-6894-3p, as well as between miR-6894-3p and SHROOM2.

These findings indicate that overexpression of lnc-MAP3K13-3:1 regulates SHROOM2 expression through targeting miR-6894-3p, thereby influencing cell proliferation, apoptosis, migration, and other cellular processes associated with HCC.

Lactate, long viewed as a byproduct of glycolysis and metabolic waste. Initially identified within the context of yogurt fermentation, lactate's role extends beyond culinary applications to its significance in biochemical processes. Contemporary research reveals that lactate functions not merely as the terminal product of glycolysis but also as a nexus for initiating physiological and pathological responses within the body. Lysine lactylation (Kla), a novel post-translational modification (PTM) of proteins, has emerged as a pivotal mechanism by which lactate exerts its regulatory influence. This epigenetic modification has the potential to alter gene expression patterns, thereby impacting physiological and pathological processes. Increasing evidence indicates a correlation between lactylation and adverse prognosis in various malignancies. Consequently, this review article aims to encapsulate the proteins that interact with lactate, elucidate the role of lactylation in tumorigenesis and progression, and explore the potential therapeutic targets afforded by the modulation of lactylation. The objective of this review is to clarify the oncogenic significance of lactylation and to provide a strategic framework for future research directions in this burgeoning field.

Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent disease caused by high fat and high cholesterol intake, which leads to systemic deterioration. The aim of this research is to conduct a psychobiological exploration of MASH in adult male rats.

Subjects who were administered a high-fat and high-cholesterol diet for 14 weeks. Then, we assessed the acoustic startle response and alertness through the prepulse inhibition paradigm as well as the associative learning by the use of the passive avoidance test. Also, we explored the astrocyte density in the prefrontal cortex and hippocampus.

Our results showed that, whereas the MASH group did not display an impaired associative learning, a lower exploration rate was found in this group. Moreover, a reduced prepulse inhibition was found in these subjects in the case of the weaker and closer-to-the-stimulus prepulse, which indicates a mild alteration in this process. No differences were found in astrocyte density in the MASH group in comparison with controls.

MASH seems to be linked with cognitive dysfunction. Further research is needed to elucidate the pathway involved in this disease and its underlying mechanism, as well as the potential implication in human health.

Hepatocellular carcinoma (HCC), a prevalent form of primary liver malignancy, arises from liver-specific hepatocytes. Senecio scandens Buch.-Ham(Climbing senecio) is a bitter-tasting plant of the Compositae family with anti-tumor properties. This study aims to identify the molecular targets and pathways through which Climbing senecio regulates HCC.

Active ingredients of Climbing senecio were collected from four online databases and mapped to relevant target databases to obtain predicted targets. After recognizing the key pathways through which Climbing senecio acts in HCC. Gene expression data from GSE54238 Underwent differential expression and weighted gene correlation network analyses to identify HCC-related genes. The "Climbing senecio-Hepatocellular Carcinoma Targets" network was constructed using Cytoscape 3.10.1 software, followed by topology analysis to identify core genes. The expression and distribution of key targets were evaluated, and the differential expression of each key target between normal and diseased samples was calculated. Moreover, single-cell data from the Gene Expression Omnibus (GSE202642) were used to assess the distribution of Climbing senecio's bioactive targets within major HCC clusters. An intersection analysis of these clusters with pharmacological targets and HCC-related genes identified Climbing senecio's primary targets for this disease. Cell communication, receiver operating characteristic (ROC)analysis, survival analysis, immune filtration analysis, and molecular docking studies were conducted for detailed characterization.

Eleven components of Climbing senecio were identified, along with 520 relevant targets, 300 differentially expressed genes, and 3765 co-expression module genes associated with HCC. AKR1B1, CA2, FOS, CXCL2, SRC, ABCC1, and PLIN1 were identified within the intersection of HCC-related genes and Climbing senecio targets. TGFβ, IL-1, VEGF, and CXCL were identified as significant factors in the onset and progression of HCC. These findings underscore the anti-HCC potential and mode of action of Climbing senecio, providing insights into multi-targeted treatment approaches for HCC.

This study revealed that Climbing senecio may target multiple pathways and genes in the process of regulating HCC and exert potential drug effects through a multi-target mechanism, which provides a new idea for the treatment of HCC. However, the research is predicated on network database analysis and bioinformatics, offering insights into HCC therapeutic potential while emphasizing the need for further validation.

Hepatocellular carcinoma (HCC) is the sixth most frequently diagnosed cancer worldwide accompanied by a low 5-year survival rate. In our study, we aimed to analyze relevant genetic features that can predict the prognosis of HCC patients by single-cell RNA sequencing (scRNA-seq).

Single-cell RNA-seq data of HCC were analyzed from the Gene Expression Omnibus (GEO) database. Using the Seurat package, we performed quality control to remove cells with low quality. After normalization, we detected highly variable genes across the single cells. Then, cell clustering and Cell type annotation were performed using highly variable genes. Then, functional enrichment analyses were performed by GO and KEGG, and cell-cell communication analysis, trajectory analysis were conducted. LASSO-Cox regression analysis was used to perform Survival analysis and ROC evaluation for high and low-risk groups. Validation of the expressions and survival prognosis of the screened genes in HCC. Expression levels of the genes were analyzed by RT-qPCR and western blot in normal liver cell line THLE-3 and HCC cell lines (HuH7, HCCLM9, and HCCLM13).

A total of 2208 up-regulated and 1447 down-regulated genes were identified in HCC samples. These differentially expressed genes (DEGs) were enriched in several cytokine-related pathways and the MIF-CD74/CXCR4 signaling pathway. By integrating large amounts of RNA sequencing data, we identified 566 prognostic genes associated with HCC cells. Eleven genes were screened using the LASSO-COX risk factor model. Stratifying patients into high- or low-risk groups based on these genes allowed us to effectively predict their survival and ROC curve. Five genes were further found to be associated with poor survival prognosis in HCC and were notably overexpressed in HCC cell lines compared to normal liver cell line.

This study revealed potential prognostic marker genes in HCC patients, providing insights into predicting patients' survival rates.

Topoisomerase is a ubiquitous enzyme in the control of DNA chain topology. There have been extensive research on topoisomerase inhibitors derived from natural sources, which act as partial inducers of tumor cell apoptosis. However, their specific efficacy in treating hepatocellular carcinoma is relatively unexplored. Hence, this comprehensive review focuses on the structural characteristics and anti-cancer properties of topoisomerase inhibitors in hepatocellular carcinoma. Furthermore, this review is also elucidating the mechanism of action, structure-activity relationships, therapeutic limitations, stage of clinical trials of described classes of natural bioactive compounds as well as their potential application in cancer chemotherapies. This broad understanding of topoisomerase medical biology will provide indispensable framework for enhancing the efficiency of rational anti-hepatocellular carcinoma drug discovery.

The emergence of sorafenib resistance has become a predominant impediment and formidable dilemma in the therapeutic approach for hepatocellular carcinoma (HCC). Although the approval of next-generation drugs as alternatives to sorafenib is a significant development, the concurrent use of inhibitors that target additional key molecular pathways remains an effective strategy to mitigate the acquisition of resistance. Here, we identified Glutathione S-Transferase Alpha 1 (GSTA1) as a critical modulator of sorafenib resistance (SR) in hepatocellular carcinoma (HCC) based on our findings from experiments conducted on recurrent liver cancer tissues, xenograft mouse models, organoids, and sorafenib-resistant cells. Elevated GSTA1 levels are strongly associated with adverse clinical prognoses. The knockout of GSTA1 reinstates sorafenib sensitivity, whereas its overexpression attenuates drug efficacy. Mechanistically, GSTA1 enhances the accumulation of lipid peroxides and suppresses ferroptosis by exerting its peroxidase function to regulate the SR. Notably, the upregulation of GSTA1 expression is mediated by the transcription factor CTNNB1 (β-catenin), resulting in the formation of a cytoplasmic complex between GSTA1 and CTNNB1. This complex facilitates the nuclear translocation of CTNNB1, establishing a positive feedback loop. The combined use of GSTA1 and CTNNB1 inhibitors demonstrated synergistic anti-tumour effects through the induction of ferroptosis both in vitro and in vivo. Our findings reveal a novel regulatory role of the GSTA1/CTNNB1 axis in ferroptosis, suggesting that targeting GSTA1 and CTNNB1 could be a promising strategy to circumvent sorafenib resistance in HCC.

Recently, numerous studies have revealed the participation of circular RNAs (circRNAs) in cancer progression. Likewise, this research focused on circRNAs in hepatocellular carcinoma (HCC). A lowly expressed circRNA hsa_circ_0072309 in HCC was screened by analyzing the circRNA microarray GSE242797 and GSE216115 and identified in clinical specimens and cells. Subsequently, CCK-8, colony formation, and transwell assays were performed. The results revealed that hsa_circ_0072309 overexpression suppressed HCC cell proliferation, migration, invasion, and sorafenib resistance, whereas its suppression showed opposite results. Mechanistic investigation found an interaction between hsa_circ_0072309 and its host gene leukemia inhibitory factor receptor (LIFR) in HCC. We found that LIFR overexpression promoted the hsa_circ_0072309 formation. In turn, hsa_circ_0072309 recruited the E1A binding protein p300 to promote the enrichment of H3K27 acetylation (H3K27ac) in the LIFR enhancer, thus transcriptionally promoting LIFR expression. To conclude, we revealed a hsa_circ_0072309/LIFR regulatory loop in HCC, which may provide a potential target for HCC treatment.

Krüppel-like factor 7 is a transcriptional activator and acts as an oncogene in human cancers, including hepatocellular carcinoma (HCC). Tryptophan metabolism is important for HCC cell proliferation, metastasis, and invasion. It is unclear whether KLF7 could regulate Trp metabolism in HCC. In this study, we found that Trp metabolism was suppressed in HCC cells with KLF7 knockdown. The mRNA and protein levels of SLC1A5, SLC7A5, and TPH1, as well as the content of Trp and serotonin, were reduced after KLF7 knockdown, and were potentiated following KLF7 overexpression. Increasing the content of serotonin could restore the malignancy of tumour cells in vitro and tumour growth in vivo. Conversely, decreasing the content of serotonin suppressed HCC cell proliferation. The binding activity of KLF7 was on the promoter of SLC1A5, and KLF7 positively regulated the expression of SLC1A5. KLF7 contributed to the proliferation and migration of HCC cells by up-regulation of SLC1A5. Collectively, KLF7 promotes the progression of HCC through regulating Trp metabolism. The newly identified axis of KLF7/ SLC1A5 in HCC could represent a potential target for HCC therapy.

Hepatocellular carcinoma (HCC) is a common malignant tumor. Histone lactylation, a novel epigenetic modification, plays a crucial role in various cancers. However, the functional role and underlying mechanism of histone lactylation in HCC progression have not yet been investigated. Histone lactylation levels in HCC tissues and cells were assessed using a densitometric kit and western blot analysis. The role of histone lactylation in cell malignant phenotypes was determined through functional assays in vitro, and a xenograft tumor model was established to verify the function of histone lactylation in vivo. ChIP assay was performed to explore the interaction between histone lactylation and endothelial cell-specific molecule 1 (ESM1). Additionally, gain-and-loss-of-function assays were conducted to investigate the regulatory role of ESM1 in HCC pathogenesis. Histone lactylation levels were increased in HCC tissues and cells, and H3K9 lactylation (H3K9la) and H3K56 lactylation (H3K56la) were identified as the histone modification sites. We observed that H3K9la and H3K56la caused abnormal histone lactylation and were associated with poor prognosis. Functionally, histone lactylation was found to promote HCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process in vitro. However, histone lactylation inhibition with 2-deoxy-d-glucose (2-DG) reduced the malignant phenotypes of HCC cells. In vivo, 2-DG treatment reduced tumor growth and metastasis in the HCC mouse model. Mechanistically, it was revealed that histone lactylation activated ESM1 transcription in HCC cells. ESM1 was expressed at a high level in HCC and exerted a carcinogenic role. Histone lactylation facilitates cell malignant phenotypes, tumor growth, and metastasis by upregulating ESM1 expression in HCC, which reveals the downstream molecular mechanism of histone lactylation and might provide a novel therapeutic target for HCC therapy.

Hepatocellular carcinoma (HCC) is identified as a common cancer type across the world and needs novel and efficient treatment. Tripterine, a well-known compound, exerts suppressive role in HCC development. However, the related molecular mechanism of tripterine in HCC remains unclear. The expression of MBNL1-AS1in HCC tissues and cells was measured via qRT-PCR assay. MTT assay was employed to estimate cell viability. Besides, cell migration as well as invasion was determined through transwell assay. Additionally, the binding ability of miR-708-5p and MBNL1-AS1or HK2 was proved by starBase database and luciferase reporter gene assay. Moreover, the HK2 level was detected by immunoblotting. MBNL1-AS1 was reduced in HCC tissues and cells. Overexpression of MBNL1-AS1 decreased the sensitivity of HCC cells to tripterine while MBNL1-AS1 silence played opposite effect. In addition, miR-708-5p was the target of MBNL1-AS1 and was down-regulated through MBNL1-AS1 in HCC cells. Moreover, miR-708-5p suppressed glycolysis rate and reduced the expression of vital glycolytic enzyme (HK2, LDHA and PKM2) in HCC cells. Furthermore, miR-708-5p reduced HK2 expression by binding to it directly. In this investigation, we proved that LncRNA MBNL1-AS1 increased the tripterine resistance of HCC cells at least partly by mediating miR-708-5p-related glycolysis. These findings revealed a potent therapeutic target for the treatment of HCC.

Liver cancer is a major health epidemic worldwide, mainly due to its high mortality rates and limited treatment options. The association of cellular senescence to tumorigenesis and the cancer hallmarks remains a subject of interest in cancer biology. The p53-p21 signalling axis is an important regulator in restoring the cell's balance by supporting tumor suppression and tumorigenesis in liver cancer. We review the novel molecular mechanisms that p53 and its downstream effector, p21, employ to induce cellular senescence, making it last longer, and halt the proliferation of damaged hepatocytes to become tumorous cells. We also examine how dysregulation of this pathway contributes to HCC pathogenesis, proliferation, survival, acquired resistance to apoptosis, and increased invasiveness. Furthermore, we comprehensively describe the molecular cross-talk between the p53-p21 signalling axis and major cell cycle signalling pathways, including Wnt/β-catenin, PI3K/Akt, and TGF-β in liver cancer and provide an overview of promising candidates for chemoprevention and future therapeutic strategies. This review article explores the roles of the p53-p21 pathway in liver cancer, examining its function in promoting cellular senescence under normal conditions and its potential role in cancer progression. It also highlights novel therapeutic drugs and drug targets within the pathway and discusses the implications for treatment strategies and prognosis in liver cancer.

Radioresistance is a common problem in the treatment of many cancers, including hepatocellular carcinoma (HCC). Previous studies have shown that circROBO1 is highly expressed in HCC tissues and acts as a cancer promoter to accelerate the malignant progression of HCC. However, the role and mechanism of circROBO1 in HCC radioresistance remain unclear.

CircROBO1, microRNA (miR)-136-5p and RAD21 expression levels were analyzed by quantitative real-time PCR. Cell function and radioresistance were evaluated by colony formation assay, cell counting kit 8 assay, EdU assay and flow cytometry. Protein expression was determined using western blot analysis. RNA interaction was analyzed by dual-luciferase reporter assay and RNA pull-down assay. In vivo experiments were performed by constructing mice xenograft models.

CircROBO1 was highly expressed in HCC, and its knockdown inhibited HCC cell proliferation and promoted apoptosis to enhance cell radiosensitivity. On the mechanism, circROBO1 could serve as miR-136-5p sponge to positively regulate RAD21. MiR-136-5p inhibitor or RAD21 overexpression reversed the regulation of circROBO1 knockdown on the radiosensitivity of HCC cells. Also, circROBO1 interference improved the radiosensitivity of HCC tumors in vivo.

CircROBO1 might be a promising target for treating HCC radioresistance.

Primary liver cancer (PLC), also known as hepatocellular carcinoma (HCC), is a common type of malignant tumor of the digestive system. Its pathological form has a significant negative impact on the patients' quality of life and ability to work, as well as a significant financial burden on society. Current researches had identified chronic hepatitis B virus infection, aflatoxin B1 exposure, and metabolic dysfunction-associated steatotic liver disease (MASLD) as the main causative factors of HCC. Numerous variables, including inflammatory ones, oxidative stress, apoptosis, autophagy, and others, have been linked to the pathophysiology of HCC. On the other hand, autoimmune regulation, inflammatory response, senescence of the hepatocytes, and mitochondrial dysfunction are all closely related to the pathogenesis of HCC. In fact, a growing number of studies have suggested that mitochondrial dysfunction in hepatocytes may be a key factor in the pathogenesis of HCC. In disorders linked to cancer, mitochondrial dysfunction has gained attention in recent 10 years. As the primary producer of adenosine triphosphate (ATP) in liver cells, mitochondria are essential for preserving cell viability and physiological processes. By influencing multiple pathological processes, including mitochondrial fission/fusion, mitophagy, cellular senescence, and cell death, mitochondrial dysfunction contributes to the development of HCC. We review the molecular mechanisms of HCC-associated mitochondrial dysfunction and discuss new directions for quality control of mitochondrial disorders as a treatment for HCC.

Hepatocellular carcinoma (HCC) is a prevalent form of liver cancer that poses significant challenges regarding morbidity and mortality rates. In the context of HCC, immune cells play a vital role, especially concerning the presentation of antigens. This review explores the intricate interactions among immune cells within HCC, focusing on their functions in antigen presentation and the modulation of T-cell responses. We begin by summarizing the strategies that HCC uses to escape immune recognition, emphasizing the delicate equilibrium between immune surveillance and evasion. Next, we investigate the specific functions of various types of immune cells, including dendritic cells, natural killer (NK) cells, and CD8+ T cells, in the process of antigen presentation. We also examine the impact of immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the pathways involving programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1), on antigen presentation, while taking into account the clinical significance of checkpoint inhibitors. The review further emphasizes the importance of immune-based therapies, including cancer vaccines and CAR-T cell therapy, in improving antigen presentation. In conclusion, we encapsulate the latest advancements in research, propose future avenues for exploration, and stress the importance of innovative technologies and customized treatment strategies. By thoroughly analyzing the interactions of immune cells throughout the antigen presentation process in HCC, this review provides an up-to-date perspective on the field, setting the stage for new therapeutic approaches.

Hepatocellular Carcinoma (HCC) is a serious primary solid tumor that is prevalent worldwide. Due to its high mortality rate, it is crucial to explore both early diagnosis and advanced treatment for HCC. In recent years, multi-omics approaches have emerged as promising tools to identify biomarkers and investigate molecular mechanisms of biological processes and diseases. In this study, we performed proteomics, phosphoproteomics, metabolomics, and lipidomics to reveal the molecular features of early- and advanced-stage HCC. The data obtained from these omics were analyzed separately and then integrated to provide a comprehensive understanding of the disease. The multi-omics results unveiled intricate biological pathways and interaction networks underlying the initiation and progression of HCC. Moreover, we proposed specific potential biomarker panels for both early- and advanced-stage HCC by overlapping our data with CPTAC database for HCC diagnosis, and deduced novel insights and mechanisms related to HCC origination and development, such as glucose depletion during tumor progression, ROCK1 deactivation and GSK3A activation.

Aim: The present study aims to develop, optimize and assess hispolon (HPN) lipid nanocapsules (LNCs), solid lipid nanoparticles (SLNs) and suspension for treating hepatocellular carcinoma (HCC).Materials & methods: It included UPLC-MS/MS, solubility, optimization, characterization, stability, in vitro and in vivo studies.Results: HPN-loaded LNCs were developed using phase-inversion and temperature cycling, while SLNs and suspension using hot homogenization and trituration methods. HPN-LNCs had a particle size (PS) of 196.9 nm, a PDI of 0.315 and a zeta potential of -24.3 mV. HPN-S2 had a PS of 199.90 nm, a PDI of 0.381 and a zeta potential of -19.1 mV. HPN-SPN3 showed a PS of 946.60 nm, a PDI of 0.31 and a zeta potential of -0.1945 mV. Stability tests over 3 months and gastric stability testing in different media showed no significant changes in PS, PDI, entrapment efficiency (EE) and loading capacity (LC). HPN-LNCs demonstrated 96.22% sustained drug release over 25 h, outperforming HPN-S2 (87.12%) and HPN-SPN3 (22% within 2 h). HPN-loaded LNCs improved oral bioavailability by 2.03-times, the most effective hepatoprotective action and higher localization in liver tumors over HPN-S2 and HPN-SPN3.Conclusion: HPN-Loaded LNCs results are promising, but more safety data needed in the future.

One of the most prevalent pathological types of Primary Liver Cancer (PLC) is the Hepatocellular Carcinoma (HCC) poses a global health issue. The high recurrence and metastasis rate of HCC, coupled with a low 5-year survival rate, result in a bleak prognosis. Exosomes, small extracellular vesicles released by various cells, contain diverse non-coding RNA molecules, including circular RNAs (circRNAs), which play a significant role in intercellular communication and can impact HCC progression. Studies have revealed the potential clinical applications of exosomal circRNAs as biomarkers and therapeutic targets for HCC. These circRNAs can be transferred via exosomes to nearby non-cancerous cells, thereby regulating HCC progression and influencing malignant phenotypes, such as cell proliferation, invasion, metastasis, and drug resistance. This review provides a comprehensive overview of the identified exosomal circRNAs, highlighting their potential as non-invasive biomarkers for HCC, and suggesting new perspectives for HCC diagnosis and treatment. The circRNA from exosomal organelles promotes metastasis and immune scape because of their unique chirality which is different from the Biomolecular Homochirality.

The search for novel tumor biomarkers and targets is of significant importance for the early clinical diagnosis and treatment of Hepatocellular Carcinoma (HCC). The mechanisms by which ATP citrate lyase (ACLY) promotes HCC progression remain unclear, and the connection between ACLY and REGγ has not been reported in the literature. In vitro, we will perform overexpression/knockdown of ACLY or overexpression/knockdown of REGγ to investigate the impact of ACLY on HCC cells and its underlying mechanisms. In vivo, we will establish mouse tumor models with overexpression/knockdown of ACLY or overexpression/knockdown of REGγ to study the effect of ACLY on mouse tumors and its mechanisms. Firstly, ACLY overexpression upregulated REGγ expression and activated the REGγ-proteasome pathway, leading to changes in the expression of downstream signaling pathway proteins. This promoted HCC cell proliferation, invasion, and migration in vitro, as well as tumor growth and metastasis in vivo. Secondly, ACLY overexpression increased acetyl-CoA production, upregulated the acetylation level of the REGγ promoter region histone H3K27ac, and subsequently induced REGγ expression. Lastly, enhanced acetylation of the REGγ promoter region histone H3K27ac resulted in upregulated REGγ expression, activation of the REGγ-proteasome pathway, changes in downstream signaling pathway protein expression, and promotion of HCC cell proliferation, invasion, and migration in vitro, as well as tumor growth and metastasis in vivo. Conversely, REGγ knockdown reversed these effects. ACLY and REGγ may serve as potential biomarkers and clinical therapeutic targets for HCC.

One of the most prevalent cancers worldwide is HCC, which has put patient health at risk. Increasing evidence indicated that messenger RNAs (mRNAs) played significant roles in modulating tumorigenesis. It has been established that Gli1 acts as an oncogene in a number of malignancies. However, more research was necessary to understand the Gli1 regulation mechanism in HCC.

Microarray technology was used to evaluate the expression of mRNAs. RT-qPCR was utilized to evaluate Gli1 and miR-875-5p expression. To investigate the role of Gli1, tests using CCK-8, EdU, transwell, immunofluorescence, and Western blot analysis was performed. RIP, RNA pull down, and luciferase reporter assays were employed to verify the interaction between Gli1 and miR-875-5p.

In tissues and cells of HCC, Gli1 expression appeared to be upregulated, especially in metastatic samples and advanced stages of the disease. A worse outcome was predicted by elevated Gli1 expression. Additionally, in HCC, Gli1 inhibition impeded the growth, migration, and development of the EMT. Since miR-875-5p was shown to have a molecular target in Gli1, miR-875-5p mediated the negative regulation of Gli1. In HCC tissues, its expression pattern was less prominent. In HCC tissues, there was an inverse relationship between Gli1 expression and miR-875-5p expression. Overexpressing Gli1 helped to partially counteract the suppression of HCC migration, proliferation, and EMT formation by miR-875-5p overexpression.

MiR-875-5p in HCC suppresses tumors by downregulating Gli1, which supplies a novel treatment for HCC patients.

Hepatocellular carcinoma (HCC), ranking as the second-leading cause of global mortality among malignancies, poses a substantial burden on public health worldwide. Anoikis, a type of programmed cell death, serves as a barrier against the dissemination of cancer cells to distant organs, thereby constraining the progression of cancer. Nevertheless, the mechanism of genes related to anoikis in HCC is yet to be elucidated.

This paper's data (TCGA-HCC) were retrieved from the database of the Cancer Genome Atlas (TCGA). Differential gene expression with prognostic implications for anoikis was identified by performing both the univariate Cox and differential expression analyses. Through unsupervised cluster analysis, we clustered the samples according to these DEGs. By employing the least absolute shrinkage and selection operator Cox regression analysis (CRA), a clinical predictive gene signature was generated from the DEGs. The Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to determine the proportions of immune cell types. The external validation data (GSE76427) were procured from Gene Expression Omnibus (GEO) to verify the performance of the clinical prognosis gene signature. Western blotting and immunohistochemistry (IHC) analysis confirmed the expression of risk genes.

In total, 23 prognostic DEGs were identified. Based on these 23 DEGs, the samples were categorized into four distinct subgroups (clusters 1, 2, 3, and 4). In addition, a clinical predictive gene signature was constructed utilizing ETV4, PBK, and SLC2A1. The gene signature efficiently distinguished individuals into two risk groups, specifically low and high, demonstrating markedly higher survival rates in the former group. Significant correlations were observed between the expression of these risk genes and a variety of immune cells. Moreover, the outcomes from the validation cohort analysis aligned consistently with those obtained from the training cohort analysis. The results of Western blotting and IHC showed that ETV4, PBK, and SLC2A1 were upregulated in HCC samples.

The outcomes of this paper underscore the effectiveness of the clinical prognostic gene signature, established utilizing anoikis-related genes, in accurately stratifying patients. This signature holds promise in advancing the development of personalized therapy for HCC.

The early diagnosis of liver cancer is crucial for the treatment and depends on the coordinated use of several test procedures. Early diagnosis is crucial for precision therapy in the treatment of the hepatocellular carcinoma (HCC). Therefore, in this study, the NK cell-related gene prediction model was used to provide the basis for precision therapy at the gene level and a novel basis for the treatment of patients with liver cancer. Natural killer (NK) cells have innate abilities to recognize and destroy tumor cells and thus play a crucial function as the "innate counterpart" of cytotoxic T cells. The natural killer (NK) cells is well recognized as a prospective approach for tumor immunotherapy in treating patients with HCC. In this research, we used publicly available databases to collect bioinformatics data of scRNA-seq and RNA-seq from HCC patients. To determine the NK cell-related genes (NKRGs)-based risk profile for HCC, we isolated T and natural killer (NK) cells and subjected them to analysis. Uniform Manifold Approximation and Projection plots were created to show the degree of expression of each marker gene and the distribution of distinct clusters. The connection between the immunotherapy response and the NKRGs-based signature was further analyzed, and the NKRGs-based signature was established. Eventually, a nomogram was developed using the model and clinical features to precisely predict the likelihood of survival. The prognosis of HCC can be accurately predicted using the NKRGs-based prognostic signature, and thorough characterization of the NKRGs signature of HCC may help to interpret the response of HCC to immunotherapy and propose a novel tumor treatment perspective.

Even though RNA treatments were first proposed as a way to change aberrant signaling in cancer, research in this field is currently ongoing. The term "RNAi" refers to the use of several RNAi technologies, including ribozymes, riboswitches, Aptamers, small interfering RNA (siRNA), antisense oligonucleotides (ASOs), and CRISPR/Cas9 technology. The siRNA therapy has already achieved a remarkable feat by revolutionizing the treatment arena of cancers. Unlike small molecules and antibodies, which need administration every three months or even every two years, RNAi may be given every quarter to attain therapeutic results. In order to overcome complex challenges, delivering siRNAs to the targeted tissues and cells effectively and safely and improving the effectiveness of siRNAs in terms of their action, stability, specificity, and potential adverse consequences are required. In this context, the three primary techniques of siRNA therapies for hepatocellular carcinoma (HCC) are accomplished for inhibiting angiogenesis, decreasing cell proliferation, and promoting apoptosis, are discussed in this review. We also deliberate targeting issues, immunogenic reactions to siRNA therapy, and the difficulties with their intrinsic chemistry and transportation.

Mechanical stimulation is the key physical factor in cell environment. Mechanotransduction acts as a fundamental regulator of cell behavior, regulating cell proliferation, differentiation, apoptosis, and exhibiting specific signature alterations during the pathological process. As research continues, the role of epigenetic science in mechanotransduction is attracting attention. However, the molecular mechanism of the synergistic effect between mechanotransduction and epigenetics in physiological and pathological processes has not been clarified. We focus on how histone modifications, as important components of epigenetics, are coordinated with multiple signaling pathways to control cell fate and disease progression. Specifically, we propose that histone modifications can form regulatory feedback loops with signaling pathways, that is, histone modifications can not only serve as downstream regulators of signaling pathways for target gene transcription but also provide feedback to regulate signaling pathways. Mechanotransduction and epigenetic changes could be potential markers and therapeutic targets in clinical practice.

Hepatocellular carcinoma (HCC) is a primary liver malignancy commonly encountered in the setting of chronic liver disease and cirrhosis. Compound Kushen Injection (CKI) has been widely used in HCC, however, the underlying mechanisms are scarce.

To explore the molecular mechanisms of CKI for HCC.

The chemical ingredients of CKI were reviewed from published articles and the potential targets were got from Herbal Ingredients' Targets Platform. Coagulation-related targets were from Kyoto Encyclopedia of Genes and Genomes and HCC-related targets were from Therapeutic Target Database, Gene Expression Omnibus, and The Cancer Genome Atlas. Then the CKI-Herb-Target and CKI-Herb-Target-HCC networks were built. The shared targets between CKI and HCC were used for functional enrichment through Metascape and the shared coagulation-related target was used for molecular docking and survival analysis.

A total of 23 chemical ingredients and 41 potential targets shared between CKI and HCC were obtained. The results of functional enrichment indicated that several canonical pathways of CKI mostly participated in the treatment of HCC. Furthermore, a chemical ingredient of CKI formed a stable hydrogen bond link with the ASN-189 on PLG, with a best binding energy of -4.7 kcal/mol. Finally, PLG was confirmed as the shared coagulation-related target and interrelated with the prognosis of HCC.

CKI probably improves HCC prognosis through PLG. Our research undoubtedly deepened the understanding of the molecular mechanism of CKI anti-HCC.

Purinergic signaling has emerged as an important paracrine-autocrine intercellular system that regulates physiological and pathological processes in practically all organs of the body. Although this system has been thoroughly defined since the nineties, recent research has made substantial advances regarding its role in aspects of liver physiology. However, most studies have mainly targeted the entire organ, 70% of which is made up of parenchymal cells or hepatocytes. Because of its physiological role, the liver is exposed to toxic metabolites, such as xenobiotics, drugs, and fatty acids, as well as to pathogens such as viruses and bacteria. Under injury conditions, all cell types within the liver undergo adaptive changes. In this context, the concentration of extracellular ATP has the potential to increase dramatically. Indeed, this purinergic response has not been studied in sufficient detail in non-parenchymal liver cells. In the present review, we systematize the physiopathological adaptations related to the purinergic system in chronic liver diseases of non-parenchymal liver cells, such as hepatic stellate cells, Kupffer cells, sinusoidal endothelial cells, and cholangiocytes. The role played by non-parenchymal liver cells in these circumstances will undoubtedly be strategic in understanding the regenerative activities that support the viability of this organ under stressful conditions.

Liver cancer is the 4th most lethal form of cancer with a poor prognosis for patients worldwide. Dysregulation of lipid metabolism is related to FA oxidation alternation which can be modified by peroxisome proliferator-activated receptor-α (PPARα). Therefore, it is important to identify the lipid metabolism-related genes regulated by PPARα in liver cancer. Hub genes related to the lipid metabolism pathway of HCC samples treated with PPARα agonist (WY-14,643) were identified through a weighted gene co-expression network analysis (WGCNA). Gene expression and clinical information were obtained from the Gene Expression Omnibus (GEO) database. The network of top main hub genes was visualized by the Cytoscape software using MCODE and CytoHubba plugins. Finally, the expression and clinical association of each hub gene were evaluated using enrichment analysis, TCGA data, GEPIA, GSCA, and q-PCR. Based on our results, the top 5 co-expressed genes including (CPT2, ACSL1, ACSL3, ACOX1, and SLC27A2) were selected as the main hub genes participating in fatty acid metabolism, fatty acid beta-oxidation, and PPAR signaling pathway. All association of higher ACSL3 expression with lower outcomes and survival rates was detected in HCC patients. Therefore, lipid metabolism-related Hub genes regulated by PPARα are potential biomarkers, and they may offer a therapeutical foundation for targeted therapy directed against the HCC antitumor strategy.

Hepatocellular carcinoma (HCC) is one of the most common primary neoplasms of the liver and one of the most common solid tumors in the world. Its global incidence is increasing and it has become the third leading cause of cancer-related deaths. There is growing evidence that chemokines play an important role in the tumor microenvironment, regulating the migration and localization of immune cells in tissues and are critical for the function of the immune system. This review comprehensively analyses the expression and activity of chemokines in the TME of HCC and describes their interrelationship with hepatocarcinogenesis and progression. Special attention is given to the role of chemokine-chemokine receptors in the regulation of immune cell accumulation in the TME. Therapeutic strategies targeting tumor-promoting chemokines or the induction/release of beneficial chemokines are reviewed, highlighting the potential value of natural products in modulating chemokines and their receptors in the treatment of HCC. The in-depth discussion in this paper provides a theoretical basis for the treatment of HCC. It is an important reference for new drug development and clinical research.

Tumor burden score (TBS) based on maximum tumor diameter and number has been shown to correlate with prognosis in patients with hepatocellular carcinoma (HCC). Nevertheless, the results are conflicting. Hence, we conducted a meta-analysis to analyze the association between TBS and survival outcomes of HCC patients.

A comprehensively search of the databases including PubMed, Embase and Web of Science was performed to retrieve studies satisfying the inclusion criteria until August 31, 2023. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. All the data analyses were carried out by STATA 12.0.

10 retrospective studies containing 25073 patients were incorporated in the study. The results demonstrated that high TBS was markedly association with poor overall survival (OS) (HR: 1.79, 95% CI: 1.45-2.23) and relapse-free survival / progression-free survival(RFS/PFS) (HR: 1.71; 95% CI: 1.42-2.07). Subgroup analysis showed that the prognostic value of TBS in HCC was not affected by any subgroup.

TBS may be an efficient prognostic index in HCC patients.

This study aims to explore the analgesic effect of lidocaine administered through the hepatic artery during hepatic artery infusion chemotherapy (HAIC) for hepatocellular carcinoma (HCC).

A total of 45 HCC patients were randomly divided into a study group and a control group. Both groups received oxaliplatin (OXA) based FOLFOX protocol via electronic infusion pump. The study group was continuously infused with 100 mg of lidocaine during HAIC, while 5% glucose solution was infused in the same way as described above. Changes in vital signs, visual analogue score (VAS) and general comfort score (GCQ scale) were recorded before surgery (Time point 0), at the end of infusion (Time point 01), 1 h after HAIC (Time point 02), 3 h after HAIC (Time point 03) and 6 h after HAIC (Time point 04).

At each point of time from Time point 0 through Time point 04, the differences in MAP, RR and SPO2 between the two groups were not statistically significant (P > 0.05). At each point of time from Time point 01 through Time point 04, the mean VAS scores in the study group were smaller and GCQ scores were higher than those in the control group, and the differences were both statistically significant (P < 0.05).

Lidocaine infusion through the hepatic artery during HAIC effectively reduces intraoperative and postoperative pain and improves patient satisfaction with pain management, making it a valuable technique for clinical practice.