Hepatocellular Carcinoma (HCC) is a highly fatal cancer, which is the most common malignant tumor globally. Recently, tRNA-derived small RNA (tsRNA) is a type of non-coding RNA that is closely related to various diseases. However, their precise existence and function in HCC remain unclear. We investigated the role of a novel tsRNA tsRNA-Asp-5-0002 in HCC.

We screened novel tsRNAs in the TCGA database. There are significant differences in tsRNA-Asp-5-0002 expression in HCC compared with other digestive system tumors. qRT-PCR was applied to confirm the level of tsRNA-Asp-5-0002 in 150 HCC patients, 50 patients with benign liver lesions, and 120 healthy controls. tsRNA-Asp-5-0002 mimics was constructed to transfect HCC cells and explore the effect of tsRNA-Asp-5-0002 on malignant phenotype of HCC. Bioinformatics analysis was used to predict the potential regulatory pathways of tsRNA-Asp-5-0002 in HCC.

(1) tsRNA-Asp-5-0002 is down-regulated in HCC. (2) qRT-PCR detection tsRNA-Asp-5-0002 had high sensitivity and specificity. (3) Low-expressed tsRNA-Asp-5-0002 was related to TNM stage, differentiation, and LNM, and the ROC curve indicated that tsRNA-Asp-5-0002 had a better diagnostic performance for HCC. (4) tsRNA-Asp-5-0002 inhibits the proliferation and migration of HCC through the PLCB1/Wnt axis.

tsRNA-Asp-5-0002 can work as an auxiliary biomarker for HCC diagnosis. Over-expression of tsRNA-Asp-5-0002 restrains the malignant process of HCC, which may offer fresh tactics for the adjuvant treatment of HCC.

GINS4 has been identified as a regulator associated with multiple types of cancers. However, the effects of GINS4 on hepatocellular carcinoma (HCC) have not been reported.

GINS4 expression in HCC was evaluated utilizing UALCAN database. The relationship between the expression of GINS4 and the survival probability of HCC patients was analyzed using Kaplan-Meier Plotter. Cell viability was evaluated by CCK8 assay and EDU assay. qRT-PCR and western blot were performed to examine GINS4 expression. The level of cell cycle was measured by flow cytometry and western blot. Fe2+ level and ferroptosis-related proteins were measured by corresponding kits and western blot. Lipid peroxidation was explored by C11 BODIPY 581/591 probe. STRING database and HDOCK database were performed to predict the binding of GINS4 to POLE2. Immunofluorescence and western blotting was adopted for assessing cell autophagy and mTOR signaling pathway. Ki67 and GPX4 levels were measured by immunohistochemistry. The expression levels of POLE2/PI3K/AKT were assessed by western blot.

The data indicated that GINS4 expression was upregulated in HCC. Knockdown of GINS4 alleviated the proliferation and cycle and promoted ferroptosis of HuH7 cells. GINS4 was proved to bind to POLE2 and the silencing of GINS4 inhibited the expression of POLE2. GINS4 knockdown accelerated ferroptosis in HuH7 cells. POLE2 overexpression reversed the influences of GINS4 silencing on proliferation and cycle, and also ferroptosis. In addition, interference with GINS4 suppressed the activation of PI3K/AKT signaling via POLE2. In vivo experiments illustrated that GINS4 deletion suppressed HCC tumor growth, increased the GPX4 expression and restrained the Ki67 level, as well as reducing POLE2/PI3K/AKT signaling.

GINS4 silencing suppressed proliferation and cycle while promoted ferroptosis in HCC cells by regulating PI3K/AKT signaling via binding to POLE2.

Per- and polyfluoroalkyl substances (PFAS), including perfluorooctane sulfonate and perfluorooctanoic acid, are associated with adverse human effects. However, few studies have assessed the effects of PFAS mixtures on hepatocellular carcinoma (HCC). In this study, we systematically investigated the effects and underlying mechanisms of PFAS mixtures on the proliferation, migration, and invasion of HCC cells (JHH-7 and Li-7) in vitro using a combination of biological techniques and high-coverage untargeted metabolomics. A six day exposure to a 5 μM PFAS mixture significantly enhanced the malignant progression of HCC in vitro. Metabolomic analysis identified the upregulation of prostaglandin E2 (PGE2) as a key factor associated with these effects. This hypothesis was further validated using celecoxib, a PGE2 inhibitor, which reduced PGE2 levels in HCC cells, consequently slowing their migration and invasion. Additionally, mice treated with celecoxib exhibited reduced tumor volumes compared with those treated with PFAS alone. These results suggest that PFAS exposure enhances HCC malignancy through the PI3K/AKT signaling pathway via increased PGE2 production. In conclusion, a 5 μM PFAS mixture accelerates HCC proliferation and invasion; moreover, celecoxib demonstrates potential as a therapeutic agent that inhibits these effects.

Chroogomphus rutilus (C. rutilus) is a traditional Chinese medicine recorded in the book Illustrations of Medicinal Fungi in China that possesses a long history of use for the treatment of various diseases, including cancer. Esculetin (ES), the primary pharmacologically active ingredient of C. rutilus, exerts significant therapeutic effects against liver cancer (LC). Nonetheless, the underlying therapeutic mechanisms of ES against LC remain poorly understood.

To investigate the mechanisms of ES in LC treatment.

ES was isolated and identified from C. rutilus. Subsequently, related targets and mechanism of ES against LC were predicted through network pharmacology and molecular docking. The antitumor effect of ES was examined using H22 tumor-bearing mouse models. The antitumor mechanism of ES was elucidated and validated using TUNEL, enzyme-linked immunosorbent assay (ELISA), immunofluorescence analysis, Western blot (WB), and quantitative real-time polymerase chain reaction (qPCR).

The chemical structure was determined using NMR carbon and hydrogen spectra. Network pharmacology analysis indicated that ES exerted anti-LC effects via the PI3K/AKT signaling pathway and associated proteins. TUNEL and ELISA revealed that ES exhibited an obvious antitumor effect in vivo and that the levels of TNF-α, IFN-γ, IL-2, and IL-6 were significantly increased. Immunofluorescence, WB, and qPCR analyses showed that ES upregulated the protein expression of Bax, caspase-3, and caspase-9 and downregulated the protein expression of Bcl-2, VEGF, and p-AKT.

This study demonstrates that the mechanisms of ES in LC treatment include enhancing immunity, inhibiting angiogenesis, and promoting apoptosis of tumor cells.

Hepatocellular carcinoma (HCC) is a common malignancy associated with high morbidity and mortality rates worldwide. To improve the prognosis of HCC, early diagnosis is crucial. However, to date, little is known about the role of natural killer cell-related genes (NKCRGs) in predicting the prognosis of hepatocellular carcinoma patients. In this study, we identified 24 differentially expressed NKCRGs in HCC specimens from the TCGA dataset, including 22 upregulated genes and 2 downregulated genes. Functional enrichment analysis revealed that these genes were mainly involved in immune response pathways and various cancer-related pathways. Univariate analysis identified 21 prognostic NKCRGs, with eight genes (PAK1, MAP2K2, MAPK3, PLCG1, SHC1, HRAS, NRAS, and MICB) confirmed to be involved in HCC prognosis through Venn diagram analysis. A prognostic model was developed using LASSO-Cox regression, incorporating four genes (MAP2K2, SHC1, HRAS, and NRAS). The model's risk score was significantly associated with overall survival (OS) in both the TCGA and ICGC cohorts. Patients with high-risk scores had poorer OS, as demonstrated by Kaplan-Meier curves and ROC analyses. The risk score was not significantly correlated with gender or age but was higher in patients with advanced tumor grades and stages. Immune status analysis using ssGSEA showed higher enrichment scores for various immune cells and pathways in the high-risk group. Additionally, the risk score was positively correlated with the immune score, indicating its potential role in tumor microenvironment modulation. Expression analysis revealed that HRAS, SHC1, MAP2K2, and NRAS were upregulated in HCC tissues, with higher expressions of HRAS, MAP2K2, and NRAS associated with shorter OS. Knockdown experiments confirmed that silencing NRAS suppressed the proliferation of HCC cells, highlighting its potential as a therapeutic target. Overall, our findings suggest that the identified NKCRGs, particularly NRAS, play crucial roles in HCC progression and could serve as valuable prognostic markers and therapeutic targets.

Hepatocellular carcinoma (HCC) is a highly lethal malignancy associated with poor prognosis due to late-stage diagnosis and high recurrence rates. The MEX3 family genes has been implicated in various cancers; however, their roles in HCC remain largely unexplored. This study aims to systematically analyze the expression patterns, prognostic significance, and immune-related functions of MEX3A, MEX3B, MEX3C, and MEX3D in HCC using comprehensive bioinformatics approaches. We conducted a multi-level bioinformatics analysis to investigate the expression, prognostic significance, clinicopathological correlations, genetic alterations, immune associations, and functional mechanisms of MEX3 family members in HCC. Transcriptomic data from TCGA and GEO databases, along with experimental validation via qRT-PCR and Western blotting, were used to assess expression profiles. Kaplan-Meier, ROC curve, and Cox regression analyses were employed for prognostic evaluation. Co-expression, enrichment, and immune infiltration analyses further elucidated the functional and immunological relevance of MEX3 family genes. A prognostic model based on co-expressed genes was constructed and validated using LASSO and time-dependent ROC analyses. MEX3A, MEX3B, MEX3C, and MEX3D were significantly upregulated in HCC tissues compared to normal liver tissues (P < 0.05). ROC curve analysis demonstrated high diagnostic accuracy, particularly for MEX3A (AUC = 0.915). Kaplan-Meier survival analysis indicated that elevated MEX3A and MEX3C expression was associated with poorer overall survival (OS) and disease-specific survival (DSS) (P < 0.05). Mutation analysis revealed that MEX3A exhibited the highest alteration frequency (11%), primarily through gene amplifications. Immune infiltration analysis demonstrated significant correlations between MEX3 expression and multiple immune cell populations, including regulatory T cells (Tregs), cytotoxic T cells, and macrophages. Moreover, MEX3B, MEX3C, and MEX3D expression correlated with key immune checkpoint genes, including PDCD1, CD274, and CTLA4. Functional enrichment analysis revealed that MEX3 co-expressed genes were significantly involved in RNA metabolism, immune response regulation, and oncogenic signaling pathways. A 17-gene MEX3 co-expression-based prognostic model stratified patients into high- and low-risk groups with significantly different survival outcomes (AUC = 0.791 at 1 year). This study highlights the oncogenic potential of MEX3 family members in HCC and their associations with immune regulation. The findings suggest that MEX3 family genes could serve as potential biomarkers for HCC prognosis and immunotherapy responsiveness. Further experimental validation is warranted to elucidate the mechanistic roles of MEX3 family genes in HCC progression and immune evasion.

Per- and polyfluoroalkyl substances (PFAS), particularly perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), are synthetic chemicals known for their widespread use and environmental persistence. These compounds have been increasingly linked to hepatotoxicity and the development of hepatocellular carcinoma (HCC). However, the molecular mechanisms by which PFAS contribute to HCC remain underexplored.

This study employs a multi-omics approach that combines network toxicology, integrated machine learning, single-cell RNA sequencing, spatial transcriptomics, experimental validation, and molecular docking simulations to uncover the mechanisms through which PFAS exposure drives HCC. We analyzed publicly available transcriptomic data from several HCC cohorts and used differential gene expression analysis to identify targets associated with both PFAS exposure and HCC. We constructed a protein-protein interaction (PPI) network and a survival risk model, the PFAS-related HCC signature (PFASRHSig), based on integrated machine learning to identify prognostic biomarkers, with the goal of identifying core targets of PFAS in HCC progression and prognosis. RT-qPCR and immunohistochemical (IHC) staining were used to validate the expression levels of the targets in both tumor and normal tissues. Molecular docking simulations were conducted to assess the binding affinities between PFAS compounds and selected target proteins.

Functional enrichment studies revealed that PFAS targets were associated with metabolic signaling pathways, which are actively involved in lipid, glucose, drug metabolism, etc. Through integrated machine learning and PPI network analysis, we identified six genes, APOA1, ESR1, IGF1, PPARGC1A, SERPINE1, and PON1, that serve as core targets of PFAS in both HCC progression and prognosis. These targets were further validated via bulk RNA-seq, single-cell RNA-seq, and spatial transcriptomics, which revealed differential expression patterns across various cell types in the HCC tumor microenvironment. The results of RT-qPCR and IHC staining were consistent with the in silico findings. Molecular docking simulations revealed strong binding affinities between PFAS compounds and these core targets, supporting their potential roles in PFAS-induced hepatocarcinogenesis.

Our study highlights key molecular targets and pathways involved in PFAS-induced liver carcinogenesis and proposes a robust survival risk model (PFASRHSig) for HCC. These findings provide new insights into PFAS toxicity mechanisms and offer potential therapeutic targets for mitigating the health risks associated with PFAS exposure. Collectively, our findings help in advancing clinical applications by providing insights into disease mechanisms and potential therapeutic interventions.

Transarterial chemoembolization (TACE) is a primary treatment for hepatocellular carcinoma (HCC) in patients with liver cirrhosis. Prognostic markers that reliably predict outcomes in these patients post-TACE remain insufficiently defined. Systemic inflammatory markers such as the Pan-Immunological Value (PIV), Platelet-Lymphocyte Ratio (PLR), Lymphocyte-Monocyte Ratio (LMR), Neutrophil-Platelet Ratio (NPR), and Neutrophil-Lymphocyte Ratio (NLR) offer potential prognostic insights for various disease. This study aims to evaluate this markers to ascertain their predictive value in determining prognosis post-TACE.

This retrospective study involved 216 patients with HCC and cirrhosis treated with TACE at a single hospital from May 2017 to May 2023. Patients were stratified into good (n = 92) and poor prognosis groups (n = 124) based on one-year post-operative outcomes using the Response Evaluation Criteria in Solid Tumors (RECIST). We evaluated preoperative inflammatory markers, biochemical and imaging data, and utilized univariate and multivariate logistic regression analyses to determine predictive factors for prognosis.

Patients in the poor prognosis group exhibited significantly higher PIV, PLR, NLR, and NPR, and lower LMR (P < 0.05). Multivariate analysis identified PIV and NPR as the strongest independent predictors of poor prognosis (OR: 1.021, P < 0.001 and OR: 2.909, P < 0.001, respectively). ROC analysis demonstrated that PIV had the greatest predictive accuracy (AUC = 0.803).

PIV, PLR, LMR, NPR, and NLR serve as significant prognostic markers for patients with HCC undergoing TACE in the context of liver cirrhosis.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Accumulating evidence suggests that epigenetic dysregulation contributes to the initiation and progression of HCC. We aimed to investigate key epigenetic regulators that contribute to tumorigenesis and progression, providing a theoretical basis for targeted therapy for HCC. We performed a comprehensive epigenetic analysis of differentially expressed genes in LIHC from the TCGA database. We identified fibrillarin (FBL), an rRNA 2'-O-methyltransferase, as an essential contributor to HCC. A series of in vitro and in vivo biological experiments were performed to investigate the potential mechanisms of FBL. FBL knockdown suppressed the proliferation of HCC cells. In vivo studies using cell-derived xenograft (CDX), patient-derived xenograft (PDX), and diethylnitrosamine (DEN)-induced HCC models in Fbl liver-specific knockout mice demonstrated the critical role of FBL in HCC carcinogenesis and progression. Mechanistically, FBL regulates the expression of CAD in HCC cells by recruiting YY1 to the CAD promoter region. We also revealed that fludarabine phosphate is a novel inhibitor of FBL and can inhibit HCC growth in vitro and in vivo. The antitumor activity of lenvatinib has been shown to be synergistically enhanced by fludarabine phosphate. Our study highlights the cancer-promoting role of the FBL-YY1-CAD axis in HCC and identifies fludarabine phosphate as a novel inhibitor of FBL. A schematic diagram depicting the FBL-YY1-CAD signaling pathway and its regulatory role in HCC progression.

YEATS2, an evolutionarily conserved reader of histone acylation marks (H3K27ac, H3K27cr, H3K27bz), functions as a central oncogenic driver in diverse cancers, including non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and hepatocellular carcinoma (HCC). Its structurally plastic YEATS domain bridges acyl-CoA metabolism to chromatin remodeling, amplifying transcription of survival genes such as MYC, BCL2, and PD-L1. YEATS2 orchestrates malignancy-specific programs-sustaining ribosome biogenesis in NSCLC through ATAC complex recruitment, enhancing NF-κB-dependent immune evasion in PDAC, and activating PI3K/AKT-driven metabolic rewiring in HCC. Structural studies demonstrate a unique aromatic cage architecture that selectively engages diverse acylated histones. Although pyrazolopyridine-based inhibitors targeting the YEATS domain show preclinical efficacy, developing isoform-selective agents remains challenging. Clinically, YEATS2 overexpression correlates with therapy resistance and may synergize with immune checkpoint blockade. This review integrates mechanistic insights into the role of YEATS2 in epigenetic regulation, evaluates its therapeutic potential, and proposes future directions: elucidating full-length complex topologies, mapping synthetic lethal interactors, and optimizing selective inhibitors. Disrupting YEATS2-mediated epigenetic adaptation presents novel opportunities for precision cancer therapy.

Hepatocellular carcinoma (HCC) is the third most common malignant tumor after gastric cancer and esophageal cancer, which is a serious threat to human health. Methyltransferase-like protein 16 (METTL16) regulates the occurrence and development of various cancers, but its molecular mechanism in HCC has not been fully investigated.

A series of databases were used to predict gene expression, methylation sites, correlation analysis, and protein interaction analysis. Gene expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry (IHC). What's more, drug-resistant cell lines were established for drug resistance analysis. Cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and 5-ethynyl-2'-deoxyuridine (EdU) staining. Flow cytometry, transwell and wound healing assays were used for apoptosis, invasion and migration, respectively. In addition, the regulatory mechanism of METTL16 in HCC was investigated by methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP) and co-immunoprecipitation (Co-IP). Finally, constructing subcutaneous transplanted tumor in nude mice confirmed the effect of METTL16 in vivo.

METTL16 was up-regulated in HCC drug-resistant tissues and cells. Knockdown of METTL16 inhibited Cisplatin (DDP) resistance, proliferation, invasion and migration of HCC cells, but promoted apoptosis. Besides, laminin subunit alpha 4 (LAMA4), which was overexpressed in HCC drug-resistant tissues and cells, was selected as the target of METTL16. Mechanistically, METTL16 and m6A reader insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) co-regulated the m6A modification and mRNA stability of LAMA4, and LAMA4 weakened the effects of METTL16 knockdown on HCC drug-resistance. Meanwhile, LAMA4 bound to collagen type IV alpha 1 chain (COL4A1) and facilitated DDP resistance and HCC progression via COL4A1. Similarly, in vivo, METTL16 induced tumor growth, as well as LAMA4 and COL4A1 expression, and increased DDP resistance.

METTL16 and IGF2BP2 jointly mediated the m6A methylation modification of LAMA4, thereby promoting DDP resistance and malignant progression of HCC through regulation of COL4A1.

E2F Transcription Factor 1 (E2F1) is a transcription factor that plays a crucial role in the growth of many cancers, including hepatocellular carcinoma (HCC). Herein, this study probed the functions and underlying mechanisms of E2F1 in HCC tumorigenesis.

The expression profiles of E2F1 and Exosome Component 10 (EXOSC10) were detected using qRT-PCR and western blotting. Functional experiments were carried out using 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, tube formation, and sphere formation assays in vitro, as well as xenograft experiments in vivo, respectively. Stemness-related proteins were assayed using western blotting. The interaction between E2F1 and EXOSC10 was verified using bioinformatics analysis and dual-luciferase reporter assay.

E2F1 was highly expressed in HCC tissues and cells, and was associated with advanced TNM stage, distant metastasis, and short survival rate. Functionally, knockdown of E2F1 suppressed HCC cell proliferation, angiogenesis, and stemness, and induced cell apoptosis. Mechanistically, E2F1 directly bound to the promoter region of EXOSC10 to up-regulate its expression. EXOSC10 silencing impaired HCC cell proliferation, angiogenesis, and stemness. Moreover, the anticancer effects of E2F1 knockdown were reversed by EXOSC10 elevation. In vivo assay, E2F1 deficiency suppressed HCC tumor growth and eliminated cancer stemness, while these effects were abolished by EXOSC10 up-regulation.

E2F1 promotes EXOSC10 transcription and then facilitates HCC growth and cancer stemness, revealing a potential target for HCC therapy.

Background: Methyltransferase-like 3 (METTL3) and HECT and RLD domain containing E3 ubiquitin protein ligase 4 (HERC4) have been studied in the field of oncology; however, their roles and interaction in hepatocellular carcinoma (HCC) await elucidation. Methods: Initially, METTL3 and HERC4 expressions in normal and HCC samples were predicted employing the UALCAN database, and the targeting relationship between these two was explored via coimmunoprecipitation assay. Following the quantification on N6-methyladenosine (m6A) enrichment, the localization of METTL3 and HERC4 on HCC cells was visualized via immunofluorescence assay. The effects of METTL3 and HERC4 on HCC cells proliferation and migration were determined in vitro assays. METTL3 and HERC4 expressions were quantified via quantitative polymerase chain reaction, and those of metastasis-related proteins N-cadherin and vimentin were calculated with immunoblotting assay. Furthermore, the levels of angiogenic factors such as vascular endothelial growth factor and basic fibroblast growth factor were measured by enzyme-linked immunosorbent assay. Results: METTL3 and HERC4 expressed highly in HCC and their expressions were positively correlated with tumor grade. METTL3 overexpression enhanced the expression of HERC4 and promoted the proliferation and migration abilities of HCC cells. Specifically, METTL3 overexpression increased vimentin and N-cadherin expressions, while its silencing did conversely. Besides, HERC4 overexpression reversed the effects of METTL3 silencing on the proliferation and migration as well as the levels of angiogenic factors in HCC cells. Conclusion: This study reveals the upregulation of METTL3 and HERC4 expression in HCC and their role in HCC by enhancing the proliferation, migration, and angiogenesis potential of HCC cells.

Insufficient microwave ablation (IMWA) is linked to aggressive hepatocellular carcinoma (HCC) progression. An increase in lactate levels after sublethal heat stress (HS) has been confirmed in HCC. However, the role of lactate-related histone lactylation in the progression of HCC caused by sublethal HS remains unclear. Here, we found that the metastatic potential of HCC increased in a lactate-dependent manner after IMWA. Moreover, sublethal HS triggered an increase in H3K18la modification, as validated in a cell-derived xenograft mouse model and human HCC samples. By performing an integrated analysis of proteomic and transcriptomic profiles, we revealed that HCC cells exhibited increased intracellular iron ion homeostasis and developed resistance to platinum-based drugs after exposure to sublethal HS. We subsequently integrated proteomic and transcriptomic data with H3K18la-specific chromatin immunoprecipitation (ChIP) sequencing to identify candidate genes involved in sublethal heat treatment-induced HCC cell metastasis. Mechanically, an increase in H3K18la modification enhanced the transcriptional activity of NFS1 cysteine desulfurase (NFS1), a key player in iron‒sulfur cluster biosynthesis, thereby reducing the susceptibility of HCC to ferroptosis after IMWA. Knocking down NFS1 diminished the metastatic potential of sublethally heat-treated HCC cells. Additionally, NFS1 deficiency exhibited a synergistic effect with oxaliplatin, leading to the significant inhibition of the metastatic capability of HCC cells both in vitro and in vivo, regardless of sublethal HS treatment. In conclusion, our study revealed the oncogenic role of histone lactylation in HCC after IMVA. We also bridged histone lactylation with ferroptosis, providing novel therapeutic targets for HCC following microwave ablation, particularly when combined with oxaliplatin-based chemotherapy.

Abnormal glucose metabolism in tumors is a well-known form of metabolic reprogramming in tumor cells, the most representative of which, the Warburg effect, has been widely studied and discussed since its discovery. However, contradictions in a large number of studies and suboptimal efficacy of drugs targeting glycolysis have prompted us to further deepen our understanding of glucose metabolism in tumors. Here, we review recent studies on mitochondrial overload, nuclear localization of metabolizing enzymes, and intranuclear TCA (nTCA) in the context of the anomalies produced by inhibition of the Warburg effect. We provide plausible explanations for many of the contradictory points in the existing studies, including the causes of the Warburg effect. Furthermore, we provide a detailed prospective discussion of these studies in the context of these new findings, providing new ideas for the use of nTCA and mitochondrial overload in tumor therapy.

This study examines the critical role of non-coding RNAs (ncRNAs) in regulating epithelial-mesenchymal transition (EMT) in breast cancer, a prevalent malignancy with significant metastatic potential. EMT, wherein cancer cells acquire mesenchymal traits, is fundamental to metastasis. ncRNAs-such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs)-modulate EMT by influencing gene expression and signaling pathways, affecting cancer cell migration and invasion. This review consolidates recent findings on ncRNA-mediated EMT regulation and explores their diagnostic and therapeutic potential. Specifically, miRNAs inhibit EMT-related transcription factors, while lncRNAs and circRNAs regulate gene expression through interactions with miRNAs, impacting EMT progression. Given the influence of ncRNAs on metastasis and therapeutic resistance, advancing ncRNA-based biomarkers and treatments holds promise for improving breast cancer outcomes.

Chemotherapy resistance in hepatocellular carcinoma presents a significant challenge to improved patient outcomes. Identifying genes associated with chemotherapy response can enhance treatment strategies and prognostic models.

We analyzed the expression of chemotherapy response-related gene in hepatocellular carcinoma using TCGA and GSE109211 cohorts. We constructed a prognostic model using Least Absolute Shrinkage and Selection Operator (LASSO) analysis and assessed its efficacy using Kaplan-Meier survival analysis. Additionally, we evaluated the immune landscape and gene mutation profiles between different chemotherapy response-related gene (CRRG) subtypes. DNAJC8's role in hepatocellular carcinoma cell functions and chemotherapy resistance was further explored through gene knockdown experiments in vitro and in vivo.

Differential expression analysis identified 220 common genes associated with chemotherapy response. The prognostic model incorporating seven key genes efficiently distinguished responders from non-responders and indicated poorer overall survival for the CRRG-high subtype. The CRRG value correlated with tumor stage and grade, and mutation profiles showed distinct patterns between CRRG subtypes. The CRRG-high subtype exhibited an immune-suppressive phenotype with higher expression of PD-L1 and CTLA-4. High DNAJC8 expression was linked to poor prognosis in multiple cohorts. Knocking down DNAJC8 significantly inhibited hepatocellular carcinoma cell proliferation, migration, invasion, and reduced sorafenib IC50.

The seven-gene CRRG model, particularly DNAJC8, holds potential for predicting chemotherapy response and serves as a therapeutic target in hepatocellular carcinoma.

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.

Moutan cortex has demonstrated antitumor properties attributed to its bioactive compound Paeoniflorigenone (PA). Nevertheless, there is limited research on the efficacy of PA in the prevention and treatment of hepatocellular carcinoma (HCC). We aimed to investigate the potential pharmacological mechanisms of PA in the treatment of Aflatoxin B1 (AFB1)-induced hepatocarcinogenesis using network pharmacology and bioinformatics analysis approaches. Through various databases and bioinformatics analysis approaches, 34 shared targets were identified as potential candidate genes for PA in fighting liver cancer caused by AFB1. Pathway analysis revealed involvement in cell cycle, HIF-1, and Rap1 pathways. A risk assessment model was developed using LASSO regression, showing an association between the identified genes and the tumor immune microenvironment. The genes within the risk model were found to be linked to the immune response in liver cancer. Molecular docking studies indicated that PA interacts with its targets through hydrogen bonding and hydrophobic interactions. This study provides insights into the possible mechanisms of PA in liver cancer treatment and offers a predictive model for assessing the risk level of individuals with liver cancer. These findings have significant implications for the therapeutic strategies in managing liver cancer patients.

This study investigates the underlying mechanism of circKIAA1429 (hsa_circ_0084922) in hepatocellular carcinoma (HCC) progression.

circKIAA1429, SETD1A, NAP1L3, and GLIS2 expressions in HCC cells were detected by RT-qPCR or western blot. The stability of circKIAA1429 was tested after treatment with actinomycin D and Rnase R enzyme. circKIAA1429 expression was knocked down, followed by detection of cell proliferation, apoptosis, and migration/invasion using CCK-8, flow cytometry, and transwell. RIP and RNA pull-down were performed to validate the binding between circKIAA1429 and SETD1A, while ChIP analysis determined the enrichment of SETD1A and H3K4me3 or H3K27me3 on GLIS2 or NAP1L3 promoter. A nude mouse xenograft tumor model was establish to test the effect of circKIAA1429 on tumorigenicity.

circKIAA1429 and NAP1L3 were highly expressed in HCC cells, while GLIS2 was poorly expressed. Knockdown of circKIAA1429 repressed cell proliferation/invasion/migration and facilitated apoptosis. Mechanistically, circKIAA1429 directly interacted with SETD1A to reduce the enrichment of SETD1A and H3K4me3 or H3K27me3 on GLIS2 or NAP1L3 promoter, thus diminishing GLIS2 expression and elevating NAP1L3 expression. In vivo, circKIAA1429 promotes tumorigenesis via GLIS2/NAP1L3.

circKIAA1429 interacts with SETD1A to inhibit the enrichment of H3K4me3 and H3K27me3 on GLIS2 or NAP1L3 promoter, thus inhibiting/promoting the expression of GLIS2/NAP1L3 and accelerating the progression of HCC.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide and the most common form of liver cancer. Despite global efforts toward early diagnosis and effective treatments, HCC is often diagnosed at advanced stages, where conventional therapies frequently lead to resistance and/or high recurrence rates. Therefore, novel biomarkers and promising medications are urgently required. Epi-drugs, or epigenetic-based medicines, have recently emerged as a promising therapeutic modality. Since the epigenome of the cancer cells is always dysregulated and this is followed by apoptosis-resistance, reprogramming the epigenome of cancer cells by epi-drugs (such as HDAC inhibitors (HDACis), and DNMT inhibitors (DNMTis)) could be an alternative approach to use in concert with established treatment protocols. C-FLIP, an anti-apoptotic protein, and Ku70, a member of the DNA repair system, bind together and make a cytoplasmic complex in certain cancers and induce resistance to apoptosis. Many epi-drugs, such as HDACis, can dissociate this complex through Ku70 acetylation and activate cellular apoptosis. The novel compounds for dissociating this complex could provide an innovative insight into molecular targeted HCC treatments. In this review, we address the innovative therapeutic potential of targeting c-FLIP/Ku70 complex by epi-drugs, particularly HDACis, to overcome apoptosis resistance of HCC cells. This review will cover the mechanisms by which the c-FLIP/Ku70 complex facilitates cancer cell survival, the impact of epigenetic alterations on the complex dissociation, and highlight HDACis potential in combination therapies, biomarker developments and mechanistic overviews. This review highlights c-FLIP ubiquitination and Ku70 acetylation levels as diagnostic and prognostic tools in HCC management.

BackgroundHepatocellular carcinoma (HCC) is a primary cancer, accounting for 90% of primary liver cancer, mainly occurring in patients with cirrhosis and chronic liver disease.ObjectiveTo investigate the latent mechanisms of hepatocellular carcinoma (HCC) and find therapeutic targets.MethodsDifferentially expressed and overall survival related genes of HCC, and cell death related genes were intersected to obtain latent target genes. These genes were analyzed using ROC curve for diagnosing HCC. RT-qPCR and Western blot were performed to detect the expression level of genes. Wound healing tests were performed with or without si-HSPA4. Potential ceRNA axis was forecasted using TargetScan and miRanda and the dual luciferase reporter gene assay was used to verify the results. Finally, the images of H&E dye liquor-stained HCC tissue section, the CT images for patients in different tumor stage.ResultsLINC01004/hsa-miR-125b-2-3p/HSPA4 axis was forecasted and then was verified using dual-luciferase reporter assay. HSPA4 knockdown caused significant reduction of cell proliferation and ferroptosis. Si-HSPA4 related ferroptosis was generated through impairing iron transport via targeting restrain GPX4. For human subjects, the RT-qPCR analysis revealed the that the larger the tumor diameter, the higher the LINC01004, HSPA4, and GPX4 expression, and the lower the hsa-miR-125b-2-3p expression.ConclusionLINC01004/hsa-miR-125b-2-3p/HSPA4 regulatory axis involved in the ferroptosis of the progression of HCC via GPX4 dependent method, providing new therapeutic targets for HCC patients.

GI (Gastrointestinal) malignancies are one of the most common and lethal cancers globally. The dawn of precision medicine and developing technologies have reduced the mortality rates for GI malignancies, underscoring the main role of early detection methods for survival rate improvement. Artificial intelligence (AI) is a new technology that may improve GI cancer screening, treatment, and therapeutic efficiency for better patient care. AI could accelerate the development of targeted therapies by analyzing considerable data from the genome and identifying biomarkers connected with GI tumors. This opens up new avenues toward more tailored and personalized approaches, raising efficacy while reducing undesired side effects. For instance, AI may improve treatment outcomes by accurately predicting patient responses to therapeutic regimens, helping oncologists choose the most effective treatment options. This review will outline the transformative potential of AI in GI oncology by emphasizing the incorporation of AI-based technologies to enhance patient care.

This study categorizes pollutant-induced inflammation-cancer transition into three stages: non-alcoholic fatty liver disease (NAFLD), liver fibrosis, and hepatocellular carcinoma (HCC). It systematically reveals the temporal heterogeneity of pollutant-induced liver damage. The findings indicate that pollutants not only directly damage hepatocytes but also modulate key cells in the immune microenvironment, such as hepatic stellate cells (HSCs) and Kupffer cells, thereby amplifying inflammatory and fibrotic responses, ultimately accelerating the progression of HCC. Mechanistically, in the early stage (NAFLD), pollutants primarily cause hepatocyte injury through oxidative stress and lipid metabolism dysregulation. During the fibrosis stage, pollutants promote liver fibrosis by inducing extracellular matrix accumulation, while in the HCC stage, they drive tumorigenesis via activation of the Wnt/β-catenin pathway and p53 inactivation. Through multi-omics analyses, this study identifies critical pathogenic molecules and signaling pathways regulated by pollutants, providing new insights into their pathogenic mechanisms, potential biomarkers, and therapeutic targets. These findings offer valuable guidance for the development of diagnostic and therapeutic strategies for liver diseases and the formulation of environmental health risk prevention measures.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally, and its progression is associated with various factors, including parasitic infections such as Clonorchis sinensis (C. sinensis). Although C. sinensis infection has been implicated in HCC, the molecular mechanisms, particularly the role of microRNAs (miRNAs), remain poorly understood. This study aims to fill this gap by investigating the miRNA expression profiles in C. sinensis+ and C. sinensis- HCC tissues.

We performed miRNA sequencing on HCC tissues from C. sinensis+ and C. sinensis- patients, followed by bioinformatics analyses to identify differentially expressed miRNAs (DEMs) and their target genes. Gene Ontology (GO) enrichment analysis was conducted to explore relevant biological processes, while a competitive endogenous RNA (ceRNA) network was constructed to investigate the interactions among miRNAs, long noncoding RNAs (lncRNAs), and messenger RNAs (mRNAs). Additionally, we performed survival analysis using Gene Expression Profiling Interactive Analysis 2 (GEPIA2) based on the The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and assessed the clinical relevance of DEMs. Key miRNAs identified from this analysis were further validated through quantitative real‑time polymerase chain reaction (qRT-PCR) assays to confirm their expression in MHCC97H.

Our research identified significant miRNA dysregulation in C. sinensis+ HCC tumors compared with C. sinensis- HCC tumors. Notably, miR-143-3p, miR-10a-5p, and miR-100-5p were upregulated in C. sinensis+ HCC, contributing to immune responses and tumor progression, while let-7 family members and miR-221-3p were downregulated, affecting metabolic pathways. GO enrichment analysis highlighted the involvement of developmental processes, immune system regulation, and metabolic reprogramming in C. sinensis+ HCC. The construction of a ceRNA network revealed key interactions between miRNAs, lncRNAs, and mRNAs in C. sinensis+ HCC, suggesting regulatory mechanisms that could be potential therapeutic targets. Additionally, validation through qRT-PCR confirmed these findings, highlighting miRNA dysregulation as a critical factor in C. sinensis+ HCC progression.

This study provides novel insights into the role of miRNAs in C. sinensis-infected HCC progression. The findings highlight the critical role of miRNA dysregulation in the progression of C. sinensis-associated HCC, emphasizing the potential for therapeutic interventions targeting these molecular alterations in affected patients.

Hepatocellular carcinoma (HCC) is characterized by high incidence, significant mortality, and marked heterogeneity, making accurate molecular subtyping essential for effective treatment. Using multi-omics data from HCC patients, we applied diverse clustering algorithms to identify three HCC subtypes (HSs) with distinct prognostic characteristics. Among these, HS1 emerged as an immune-compromised subtype associated with the poorest prognosis. Additionally, we developed a novel, robust, and highly accurate machine learning-guided prognostic signature (MLPS) by integrating multiple machine learning algorithms and their combinations. Our study also identified SLC2A1, the core gene of MLPS, as being highly expressed during advanced stages of tumor progression. Knockdown experiments demonstrated that reducing SLC2A1 expression significantly suppressed the malignant behavior of HCC cells. Furthermore, SLC2A1 expression was linked to responsiveness to dasatinib and vincristine, suggesting potential therapeutic relevance. MLPS and SLC2A1 offer promising tools for individualized prognosis prediction and targeted therapy in HCC, providing new opportunities to improve patient outcomes.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and its onset and progression are closely associated with epigenetic modifications, particularly post-translational modifications of histones (HPTMs). In recent years, advances in mass spectrometry (MS) have revealed a series of novel HPTMs, including succinylation (Ksuc), citrullination (Kcit), butyrylation (Kbhb), lactylation (Kla), crotonylation (Kcr), and 2-hydroxyisobutyrylation (Khib). These modifications not only expand the histone code but also play significant roles in key carcinogenic processes such as tumor proliferation, metastasis, and metabolic reprogramming in HCC. This review provides the first comprehensive analysis of the impact of novel HPTMs on gene expression, cellular metabolism, immune evasion, and the tumor microenvironment. It specifically focuses on their roles in promoting tumor stem cell characteristics, epithelial-mesenchymal transition (EMT), and therapeutic resistance. Additionally, the review highlights the dynamic regulation of these modifications by specific enzymes, including "writers," "readers," and "erasers."

Fluctuating N(6)-methyladenosine (m6A) levels affect the progression of hepatocellular carcinoma (HCC). METTL14, a m6A methyltransferase, acts as a tumor suppressor in HCC; however, its underlying mechanisms need further clarification. This study aimed to clarify the role of METTL14 in HCC and the underlying molecular mechanism. Cellular behaviors were evaluated using cell counting kit-8, EdU, and Transwell assays. The molecular mechanism was analyzed using methylated RNA binding protein immunoprecipitation, dual-luciferase reporter assay, and RNA stability determination. The results demonstrated that METTL14 expression was decreased in HCC tissues and cells, and its overexpression suppressed cellular proliferation, migration, and invasion. Moreover, RPLP2 was negatively correlated to METTL14, and it was highly expressed in HCC tissues and cells. METTL14 promoted the m6A modification of RPLP2 and reduced its stability, thereby inhibiting malignant behaviors. Besides, YTHDC2 decreased RPLP2 expression and reversed the stability induced by METTL14. In conclusion, METTL14 inhibits HCC progression by regulating the YTHDC2-m6A-RPLP2 axis.

Hepatocellular carcinoma has a high incidence and poor prognosis. In this study, we investigated the value of T-cell-related genes in prognosis by single-cell sequencing data in hepatocellular carcinoma. Twelve cases of hepatocellular carcinoma single-cell sequencing were included in the study. The high dimensional weighted gene co-expression network analysis (hdWGCNA) was used to identify gene modules associated with CD4+ T cells, CD8+ T cells and exhausted T cells. Altered signaling pathway activity in exhausted T cells was uncovered by the AUCell algorithm. xCELL, TIMER, QUANTISEQ, CIBERSORT and CIBERSORT-abs were performed to explore immune cell infiltration. Immune checkpoint inhibitor genes and TIDE methods were used to predict immunotherapy response. Finally, immunohistochemistry and real-time PCR were used to verify gene expression. The hdWGCNA algorithm identified 40 genes strongly associated with CD4+ T cells, CD8+ T cells and exhausted T cells. Seven genes were finally selected for transcriptome data modeling. The results of the three independent datasets suggested that the model had strong prognostic value. Model genes were critical factors influencing CD4+ T cell and CD8+ T cell infiltration in patients. The efficacy of PD-1 immunotherapy was higher in patients belonging to the low-risk group. Alterations in signaling pathways' activity within exhausted T cells were crucial factors contributing to the decline in immune function. Differential expression of seven genes in CD8+ T cells, CD4+ T cells and exhausted T cells were key targets for improving immunotherapy response in HCC.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Hepatitis B virus (HBV) is the main pathogen for HCC development. HBV covalently closed circular DNA (cccDNA) forms extra-host chromatin-like minichromosomes in the nucleus of hepatocytes with host histones, non-histones, HBV X protein (HBx) and HBV core protein (HBc). Epigenetic alterations are dynamic and reversible, which regulate gene expression without altering the DNA sequence and play a pivotal role in the regulation of HCC onset and progression. The aim of this review is to elucidate the deregulation of epigenetic mechanisms involved in the pathogenesis of HBV-related HCC (HBV-HCC), including post-translational histone and non-histone modifications, DNA hypermethylation and hypomethylation, non-coding RNA modification on HBV cccDNA minichromosomes and host factors, effecting the replication/transcription of HBV cccDNA and transcription/translation of host genes, and thus HBV-HCC progression. It is expected that the epigenetic regulation perspective provides new ways for more in-depth development of therapeutic control of HBV-HCC.

Liver metastasis is a common cause of death in colorectal cancer (CRC) patients, but epigenetic remodeling and metabolic reprogramming for CRC liver metastasis remain unclear. The study revealed that the Lyn/RUVBL1 complex is highly expressed in CRC and is closely correlated with liver metastasis. On the one hand, ATAC-seq and HiCut suggested that Lyn/RUVBL1 regulates the expression of TRIB3 through the POL II-mediated chromatin conformation of TRIB3 and thus the expression of β-catenin. This promotes the proliferation and migration of CRC through β-catenin-mediated upregulation of MMP9 and VEGF. On the other hand, metabolomics revealed that Lyn/RUVBL1 regulates the expression of PGE2 through the enzyme COX2, thereby promoting arachidonic acid (AA) metabolism. CUT-Tag showed that Lyn/RUVBL1 silencing reduces the H3K27ac level in the COX2 promoter. Then, it is found that COX2 is regulated by the transcription factor FOXA1. Lyn/RUVBL1 modulates AA metabolism by regulating the chromatin accessibility of FOXA1. AA metabolism promotes the metastasis of CRC by affecting β-catenin nuclear translocation and upregulating MMP9 and VEGF. These findings suggest that the Lyn/RUVBL1 complex mediates epigenetic remodeling to regulate the metabolic reprogramming of AA, highlighting its role in promoting the metastasis of CRC.

The progestin and adipoQ receptor family member, PAQR11, is recognized for its roles in vesicle trafficking, mitogenic signaling, and metastatic spread, positioning it as a crucial regulator in cancer biology. PAQR11 influences lipid metabolism and susceptibility to ferroptosis in cancer cells. This study aims to investigate the prognostic significance of PAQR11, its relevance to immune responses, and its association with drug sensitivity across various cancer types. By elucidating these aspects, the research seeks to assess PAQR11's potential as a biomarker and therapeutic target in oncology.

We conducted a comprehensive bioinformatics analysis using publicly available pan-cancer datasets from TCGA, GEO, UALCAN, TIMER, GEPIA2, KM plotter, and TISIDB. This analysis encompassed gene expression profiles across 33 cancer types, with a focus on PAQR11's expression patterns, prognostic significance, and immunological relevance. In addition, the study explored the correlation between PAQR11 expression and drug sensitivity, alongside its molecular and pathological characteristics in various tumors.

Our findings demonstrate elevated PAQR11 expression levels across multiple cancer types, which significantly correlate with patient prognostic outcomes. The analysis further revealed PAQR11's involvement in immunological and epigenetic processes, underscoring its critical role in cancer progression and treatment response. Notably, a strong correlation between PAQR11 expression and drug sensitivity was identified, suggesting its potential influence on the initiation and progression of various cancers and highlighting its promise as a therapeutic target.

The comprehensive analysis of PAQR11 underscores its significance as a biomarker for cancer prognosis and its role in regulating immunological and epigenetic processes. These findings offer valuable insights that could inform early detection strategies and the development of novel therapeutic approaches. Further exploration and validation of PAQR11 are essential, highlighting the need for its integration into future oncological research and treatment strategy development.

Not applicable.

In this review, we explore the application of next-generation sequencing in liver cancer research, highlighting its potential in modern oncology. Liver cancer, particularly hepatocellular carcinoma, is driven by a complex interplay of genetic, epigenetic, and environmental factors. Key genetic alterations, such as mutations in TERT, TP53, and CTNNB1, alongside epigenetic modifications such as DNA methylation and histone remodeling, disrupt regulatory pathways and promote tumorigenesis. Environmental factors, including viral infections, alcohol consumption, and metabolic disorders such as nonalcoholic fatty liver disease, enhance hepatocarcinogenesis. The tumor microenvironment plays a pivotal role in liver cancer progression and therapy resistance, with immune cell infiltration, fibrosis, and angiogenesis supporting cancer cell survival. Advances in immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies have shown potential, but the unique immunosuppressive milieu in liver cancer presents challenges. Dysregulation in pathways such as Wnt/β-catenin underscores the need for targeted therapeutic strategies. Next-generation sequencing is accelerating the identification of genetic and epigenetic alterations, enabling more precise diagnosis and personalized treatment plans. A deeper understanding of these molecular mechanisms is essential for advancing early detection and developing effective therapies against liver cancer.

Liver cancer, namely hepatocellular carcinoma (HCC), is a major global health concern deeply influenced by environmental factors. Air pollutants emerged as significant contributors to its incidence. This review explores the association between air pollution-specifically particulate matter (PM2.5), industrial chemicals like vinyl chloride, and benzene-and the increased risk of liver cancer. Mechanistically, air pollutants may cause liver damage by inducing oxidative stress, inflammation, and genetic mutations, contributing to cancer development. Epidemiological evidence from cohort and geographic studies highlights a positive correlation between long-term exposure to air pollutants and elevated incidence and mortality of liver cancer. Furthermore, air pollution has been shown to worsen survival outcomes in liver cancer patients, particularly those diagnosed at early stages. The review emphasizes the need for stricter air quality regulations and relevant research for underlying mechanisms exposed to air pollution. Addressing air pollution exposure could be crucial for reducing liver cancer risks and improving public health outcomes.

With the increasing impact of hepatocellular carcinoma (HCC) on society, there is an urgent need to propose new HCC diagnostic biomarkers and identification models. Histone lysine lactylation (Kla) affects the prognosis of cancer patients and is an emerging target in cancer treatment. However, the potential of Kla-related genes in HCC is poorly understood.

A variety of machine learning methods were used to construct and validate a model of differentially expressed Kla genes with comprehensive evaluations included ROC, Kaplan‒Meier curve, Cox regression, decision curve. Immune infiltration gathered with spatial transcriptome was performed using integrated data from multiple databases. Furthermore, single-cell analysis was used to discover the cell-cell communication and Mendelian randomization was used to study the causal relationships between immune cell and HCC. Lastly, qRT-PCR was used to verify the expression of Kla genes.

We established a model consisting of 12 genes that had well prognostic performance and were identified as independent prognostic factors. Single-cell analysis showed that CD8 T+ cells and conventional dendritic cells were enriched in HCC patients. Spatial transcriptomics analysis indicated that the Kla genes influenced the immune characteristics of HCC. Mendelian randomization results showed that TBNK and monocytes were the main risk factors. qRT-PCR validation results indicated that the expression of multiple genes in Huh7 cells was significantly higher than in LO2 cells.

Overall, a Kla-related model was established, which may provide new strategies and insights for the treatment and diagnosis of HCC.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Treating HCC is challenging because of the poor drug effectiveness and the lack of tools to predict patient responses. To resolve these issues, we established a patient-centric spheroid model using HepG2, TWNT-1, and THP-1 co-culture, that mimics HCC phenotype. We developed a target-independent cell killing (TICK) exclusion strategy to monitor the therapeutic response. We demonstrated that our model reproduced the Barcelona Clinic Liver Cancer (BCLC) molecular classification, displayed known alterations of epigenetic players, and responded to tyrosine kinase inhibitors (TKIs) such as sorafenib, cabozantinib, and lenvatinib in a patient-dependent manner. Importantly, we reported for the first time that our model correctly predicted 34 clinical outcomes to TKIs out of 37 case studies on 32 HCC patients confirming that patient-centric spheroids, combined with our TICK exclusion strategy, are valuable models for drug discovery and opening a near perspective to personalized care.

To compare outcomes of LLR in VI/VII of the liver in Left-lateral Decubitus Jackknife Position (LDJP) and traditional Supine Position (SP). We used propensity score matching (PSM) to analyze clinical outcomes.

This study retrospectively analyzed patients undergoing LLR for liver tumors in segments VI and/or VII at Shandong Provincial Hospital from 2018 to 2023. A total of 218 cases were included (LDJP, n = 94; SP, n = 124). Matched 1:1 PSM groups were created and clinical indicators compared between groups.

218 LLR patients, 94 LDJP and 124 supine. After 1:1 PSM, each group had 62 patients. No significant differences in clinical or laboratory parameters. All surgeries were successful, 1 LDJP conversion to open resection and 4 SP conversions (P = 0.375). LDJP average surgery duration: 220.6 ± 29.9 min, supine position: 262.6 ± 35.6 min (P < 0.001). LDJP perioperative blood loss: 169.0 ± 74.4 mL, supine position: 231.6 ± 84.6 mL (P < 0.001). Four LDJP patients required intraoperative blood transfusion compared to 16 supine position patients (P = 0.012). All cases had negative margins postoperatively. No significant differences in postoperative complications (8 LDJP vs 9 supine, P = 0.675) or length of hospital stay (25 LDJP vs 26 supine, ≥ 7 days) (P = 1.000).

Laparoscopic partial hepatectomy in LDJP for hepatic VI/VII tumor safe and feasible. Reduces operative time, blood loss, transfusion requirement, improving outcomes.

Deregulation of m6A methylation, the most prevailing RNA modification, participates in cancer pathogenesis. METTL16, an atypical methyltransferase, functions as a pro-tumorigenic factor in hepatocellular carcinoma (HCC). Here, we explored the action of METTL16 on HCC glycolysis and the associated mechanism.

Expression analysis was done by quantitative PCR, immunoblotting, or immunohistochemistry. Cell sphere formation, invasiveness, apoptosis, proliferation and viability were detected by sphere formation, transwell, flow cytometry, EdU and CCK-8 assays, respectively. Xenograft studies were performed to analyze the role in vivo. Methylated RNA immunoprecipitation (MeRIP) and RIP assays were used to verify the METTL16/PFKM relationship. PFKM mRNA stability was tested by actinomycin D treatment. Chromatin immunoprecipitation (ChIP) and luciferase assays were performed to analyze the POU3F2/METTL16 relationship.

In HCC, METTL16 expression was elevated, and increased levels of METTL16 transcript predicted poor HCC prognosis. METTL16 deficiency resulted in suppressed HCC cell growth, invasiveness and sphere formation. Moreover, METTL16 depletion diminished HCC cell glycolysis. Mechanistically, PFKM expression was positively associated with METTL16 expression. METTL16 mediated m6A methylation to stabilize PFKM mRNA via an IGF2BP3-dependent manner. Restored PFKM expression exerted a counteracting effect on METTL16 deficiency-mediated in vitro cell phenotype alterations and in vivo xenograft growth suppression. Furthermore, POU3F2 promoted the transcription of METTL16 in HCC cells.

Our findings define the crucial role of the POU3F2/METTL16/PFKM axis in HCC pathogenesis, offering the potential opportunity to combat HCC.

Since telomere length and DNA methylation both correlate with hepatocellular carcinoma (HCC) prognosis, telomere-methylation genes could be novel prognostic markers for HCC.

This study first investigated the interaction between telomere length and DNA methylation in HCC through Mendelian randomization analysis. Then, this study identified telomere-methylation genes in HCC by employing the TCGA-LIHC cohort, and explored the expression patterns of these genes in the tumor microenvironment of HCC and potential underlying mechanisms. Finally, the HCC risk-scoring model and prognostic model based on these genes were established, and the performance of the model was assessed.

The findings revealed a bidirectional relationship between telomere length and DNA methylation in HCC. Fifty telomere-methylation genes were identified, and the prognosis-related telomere-methylation genes were closely associated with Treg and Tprolif cell subsets within the HCC tumor microenvironment. Telomere-methylation genes could potentially impact the prognosis of HCC patients by modulating chromosome stability and regulating the cell cycle. Additionally, the constructed risk scoring model and prognostic prediction model showcased compelling clinical applicability, as evidenced by the receiver operating characteristic curve, the decision curve analysis, and the calibration curves.

This study elucidated the potential of telomere-methylation genes as prognostic biomarkers for HCC and paves the way for novel approaches in prognostication and treatment management for HCC patients.

Berberine (BBR) is an isoquinoline alkaloid extracted from Huang Lian and other herbal medicines. It has been reported to play a crucial role in multiple metabolic diseases and cancers. Programmed cell death-1 (PD-L1) is known as the immune checkpoint; immunotherapy targeting PD1/PD-L1 axis can effectively block its pro-tumor activity. However, the effect of the combined use of BBR and anti-PD-L1 on hepatocellular carcinoma (HCC) has not been reported.

Hep-3B and HCCLM3 cells were chosen as the experimental objects. To determine the potential anti-cancer activity of the combination of BBR and anti-PD-L1, we first treated v cells with BBR. The cell viability of Hep-3B and HCCLM3 with BBR treatment was measured by Cell Count Kit 8 assay. Cytometry by time-of-flight was performed to analyze tumor tissues after treatment with BBR and/or anti-PD-L1. Proliferation-, migration-, and invasion-related markers were measured by western blotting and immunohistochemistry.

The results showed that BBR significantly inhibited the proliferation of Hep-3B and HCCLM3.The combination treatment of BBR and anti-PD-L1 had a prominent inhibitory effect on HCC tumorigenesis. Cytometry by time-of-flight analysis indicated that BBR affects the immune subsets in the tumors. Besides, BBR and anti-PD-L1 inhibited the migration and invasion of HCC by inactivating the phosphorylation of Erk.

Our study proposed that the combination treatment of BBR and anti-PD-L1 markedly inhibited the tumorigenesis of HCC by Erk signaling pathway. We hope our research can provide a new strategy for the potential of BBR as a therapeutic agent in the treatment of HCC.

Interferon-induced protein 44-like (IFI44L) is regarded as an immune-related gene and is a member of interferon-stimulated genes (ISGs). They participate in network transduction, and its own epigenetic modifications, apoptosis, cell-matrix formation, and many other pathways in tumors, autoimmune diseases, and viral infections. The current review provides a comprehensive overview of the onset and biological mechanisms of IFI44L and its potential clinical applications in malignant tumors and non-neoplastic diseases.