Numerous meta-analyses have identified various risk factors for hepatocellular carcinoma (HCC), prompting a comprehensive study to synthesize evidence quality and strength.

This umbrella review of meta-analyses was conducted throughout PubMed, EMBASE, Web of Science, and Cochrane Database of Systematic Reviews. Evidence strength was evaluated according to the evidence categories criteria.

We identified 101 risk factors throughout 175 meta-analyses. 31 risk factors were classified as evidence levels of class I, II, or III. HBV and HCV infections increase HCC risk by 12.5-fold and 11.2-fold, respectively. These risks are moderated by antiviral treatments and virological responses but are exacerbated by higher HBsAg levels, anti-HBc positivity, and co-infection. Smoking, obesity, non-alcoholic fatty liver disease, diabetes, low platelet, elevated liver enzymes and liver fluke infection increase HCC risk, while coffee consumption, a healthy diet, and bariatric surgery lower it. Medications like metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), aspirin, statins, and selective serotonin reuptake inhibitors reduce HCC risk, while acid suppressive agents, particularly proton pump inhibitors, elevate it. Blood type O reduces the risk of HCC, while male gender and older age increase the risk.

HBV and HCV are major HCC risk factors, with risk mitigation through antiviral treatments. Lifestyle habits such as smoking and alcohol use significantly increase HCC risk, highlighting the importance of cessation. Certain drugs like aspirin, statins, GLP-1 RAs, and metformin may reduce HCC occurrence, but further research is needed to confirm these effects.

This study aims to develop and validate a predictive nomogram for early recurrence in hepatocellular carcinoma (HCC), utilizing gadoxetic acid-enhanced MRI and intravoxel incoherent motion (IVIM) imaging to improve preoperative assessment and decision-making.

From March 2018 and June 2022, a total of 245 patients with pathologically confirmed HCC, who underwent preoperative gadoxetic acid-enhanced MRI and IVIM, were retrospectively enrolled from two hospitals. These patients were divided into a training cohort (n = 160) and a validation cohort (n = 85). All patients were followed until death or the last follow-up date, with a minimum follow-up period of two years. Clinical indicators and pathologic information were compared between train cohort and validation cohort. Radiological features and diffusion parameters were compared between recurrence and non-recurrence groups using the chi-square test, Mann-Whitney U test and independent sample t test in training cohort. Univariate and multivariate analyses were performed to identify significant clinical-radiological variables associated with early recurrence in the training cohort. Based on these findings, a predictive nomogram integrating risk factors and diffusion parameters was developed. The predictive performance of the nomogram was evaluated in both the training and validation cohorts.

No statistically significant difference in clinical and pathologic characteristics were observed between the training and validation cohorts. In training cohort, significant differences were identified between the recurrence and non-recurrence groups in tumor size, nodule-in-nodule architecture, mosaic architecture, non-smooth tumor margin, intratumor necrosis, satellite nodule, and peritumoral hypo-intensity in the hepatobiliary phase (HBP). The results of multivariate analysis identified tumor size (HR, 1.435; 95 % CI, 0.702-2.026; p < 0.05), mosaic architecture (HR, 0.790; 95 % CI, 0.421-1.480; p < 0.05), non-smooth tumor margin (HR, 1.775; 95 % CI, 0.941-3.273; p < 0.05), intratumor necrosis (HR, 1.414; 95 % CI, 0.807-2.476; p < 0.05), satellite nodule (HR, 0.648; 95 % CI, 0.352-1.191; p < 0.01), peritumoral hypo-intensity on HBP (HR, 2.786; 95 % CI, 1.141-6.802; p < 0.001) and D (HR, 0.658; 95 % CI,0.487-0.889; p < 0.01) were the independent risk factor for recurrence. The nomogram exhibited excellent predictive performance with C-index of 0.913 and 0.875 in the training cohort and validation cohort, respectively. Also, based on the nomogram score, the patients were classified according to risk factor and the Kaplan-Meier curve analysis also showed that the nomogram had a good predictive efficacy.

The nomogram, integrating radiological risk factors and diffusion parameters, offers a reliable tool for preoperative prediction of early recurrence in HCC patients.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, emphasizing the urgent need for novel therapeutic strategies. In this study, we investigate the anti-tumor potential of CC-885, a cereblon (CRBN) modulator known for its efficacy in targeting neoplastic cells through proteasomal degradation pathways. Our findings demonstrate that CC-885 exhibits potent anti-tumor activity against HCC. In vitro assays revealed that CC-885 significantly inhibits the proliferation, migration, and invasion of HCC cells. These effects were corroborated in vivo, where CC-885 markedly suppressed tumor growth and angiogenesis in chick embryos and impeded the progression of orthotopic liver tumors in murine models. Mechanistically, CC-885 selectively reduces GOLM1 protein levels via ubiquitin-mediated proteasomal degradation. Knockdown of GOLM1 recapitulated the anti-proliferative effects of CC-885, while overexpression of GOLM1 conferred resistance to CC-885-induced apoptosis and growth inhibition. Further investigation revealed that CC-885 facilitates the interaction between GOLM1 and the E3 ubiquitin ligase CRBN, promoting the ubiquitination and subsequent degradation of GOLM1. Transcriptomic analyses showed that both CC-885 treatment and GOLM1 knockdown modulate critical pathways involved in apoptosis. These findings position CC-885 as a promising therapeutic candidate for HCC, acting primarily through CRBN-dependent degradation of GOLM1, and support its further development for clinical application.

Hepatocellular carcinoma (HCC) is the sixth most common cause of cancer globally, third most common cause of cancer-related death, and most common primary liver malignancy. Whilst nodular well-defined HCC remains the classical phenotype, presentations with infiltrative phenotype, very large HCC, and complications as tumour rupture provide immense diagnostic and therapeutic challenges. Infiltrative HCC is difficult to distinguish against the background cirrhotic liver. They are ill defined on imaging, have poor vascularity, and aggressive biological behaviour. Vascular invasion, metastasis, and poor response to loco-regional, as well as systemic therapy, leads to dismal prognosis. Very large HCCs have a relatively better prognosis than infiltrative HCC and mandate multimodal therapies to downstage for a curative response including liver transplant. Improvement in interventional radiology techniques, emerging evidence with systemic therapies including immunotherapy, and better understanding of tumour biology have opened newer avenues in the management of such complex cases. HCC rupture is a catastrophic moment in the natural history of HCC which has an exponential increase in mortality. Clinical presentation of pain abdomen, hypotension/syncope, new onset, or sudden increase in ascites mandates a strong suspicion of rupture. Presence of hemoperitoneum on diagnostic tap and contrast extravasation in a computed tomography/magnetic resonance imaging are the diagnostic hallmarks. Emergency surgical intervention, locoregional therapies in the form of bland embolisation, or chemoembolisation forms the management cornerstone. The long-term survival and liver transplant as a curative therapy still needs more data as fear of tumour spread is a possibility. This review summarises the clinical challenges with this advance HCC and provides an algorithmic approach for management.

Hydrogel, as a promising embolic material for hepatocellular carcinoma (HCC), may fully embolize both major vessels and peripheral microvessels. A self-assembling hydrogel composed of chemotherapeutic drugs offers significant clinical benefits without carrier introduction. Herein, we developed a sustained drug-releasing complex hydrogel (RKT@gel), which was fabricated by the self-assembly of raltitrexed chemotherapeutic drugs (R@gel), along with the incorporation of kaempferol and tantalum nanoparticles (Ta NPs). Kaempferol enhances the mechanical strength of R@gel and inhibits hypoxia-induced angiogenesis post-embolization, improving embolization effectiveness. In addition to enabling X-ray-guided transarterial chemoembolization (TACE), Ta NPs enhance radiation sensitivity. These synergistic effects of RKT@gel not only significantly induce immunogenic cell death, thereby enhancing the activation of dendritic cells, but also activate major histocompatibility complex class I (MHC-I)-mediated antitumor immune recognition and cytotoxicity. In vivo, RKT@gel achieves enhanced tumor deposition and sustained drug release, effectively suppressing tumor progression. Additionally, when combined with radiotherapy, RKT@gel achieves efficient antitumor immunoactivation. Overall, this versatile composite hydrogel not only achieves effective embolization therapy but also substantially triggers antitumor immune responses with good biocompatibility. This multifunctional design provides a TACE-based multidisciplinary strategy for HCC.

Adipose tissue is an immunologically active organ that controls host physiology, partly through the release of mediators termed adipokines. In obesity, adipocytes and infiltrating leukocytes produce adipokines, which include the hormones adiponectin and leptin and cytokines such as tumour necrosis factor and IL-1β. These adipokines orchestrate immune responses that are collectively referred to as metabolic inflammation. Consequently, metabolic inflammation characterizes metabolic disorders and promotes distinct disease aspects, such as insulin resistance, metabolic dysfunction-associated liver disease and cardiovascular complications. In this unifying concept, adipokines participate in the immunological cross-talk that occurs between metabolically active organs in metabolic diseases, highlighting the fundamental role of adipokines in obesity and their potential for therapeutic intervention. Here, we summarize how adipokines shape metabolic inflammation in mice and humans, focusing on their contribution to metabolic disorders in the setting of obesity and discussing their value as therapeutic targets.

To develop an MRI-based score that enables individualized predictions of the survival benefit of wide over narrow resection margins.

This single-center retrospective study (December 2011 to May 2022) included consecutive patients who underwent curative-intent resection for single Barcelona Clinic Liver Cancer (BCLC) 0/A HCC and preoperative contrast-enhanced MRI. In patients with narrow resection margins, preoperative demographic, laboratory, and MRI variables independently associated with early recurrence-free survival (RFS) were identified using Cox regression analyses, which were employed to develop a predictive score (named "MARGIN"). Survival outcomes were compared between wide and narrow resection margins in a propensity-score matched cohort for the score-stratified low- and high-risk groups, respectively.

Four hundred nineteen patients (median age, 54 years; 361 men) were included, 282 (67.3%) undergoing narrow resection margins. In patients with narrow resection margins, age, alpha-fetoprotein (AFP) > 400 ng/mL, protein induced by vitamin K absence or antagonist-II (PIVKA-II) > 200 mAU/mL, radiological involvement of liver capsule, and infiltrative appearance were associated with early RFS (p values, 0.002-0.04) and formed the MARGIN score with a testing dataset C-index of 0.75 (95% CI: 0.65-0.84). In the matched cohort, wide resection margin was associated with improved early RFS rate for the high-risk group (MARGIN score ≥ - 1.3; 71.1% vs 41.0%; p = 0.02), but not for the low-risk group (MARGIN score < - 1.3; 79.7% vs 76.1%; p = 0.36).

In patients with single BCLC 0/A HCC, the MARGIN score may serve as promising decision-making to indicate the need for wide resection margins.

The MARGIN score has the potential to identify patients who would benefit more from wide resection margins than narrow resection margins, improving the postoperative survival of patients with single BCLC 0/A hepatocellular carcinoma (HCC).

Age, AFP, PIVKA-II, radiological involvement of liver capsule, and infiltrative appearance were associated with early RFS and formed the MARGIN score. The MARGIN score achieved a testing dataset C-index of 0.75. Wide resection margins were associated with improved early RFS for the high-risk group, but not for the low-risk group.

Xanthoangelol (C25H28O4), a natural flavonoid derived from chalcones, has shown potential pharmacological activities. However, its primary interaction mechanism with proteins and cells is not well understood. In the present study, we focus on the anticancer effects of xanthoangelol against hepatocellular carcinoma (HCC) as well as its binding affinity with a plasma drug carrier protein, α2-macroglobulin. The anticancer effects of xanthoangelol on human HCC cell line HepG2 cells were assayed using MTT, LDH, qPCR, and caspase activity assays. Efficient binding of the xanthoangelol with α2-macroglobulin was established by experimental and molecular docking studies. It was found that xanthoangelol significantly mitigates cell viability through upregulating intrinsic (Bax/Bcl-2, caspase-9) and extrinsic (caspase-8) apoptotic pathways. Moreover, it was detected that xanthoangelol induces ER stress through the upregulation of CHOP in HepG2 cells. Fluorescence spectra show that xanthoangelol strongly interacts with α2-macroglobulin mediated by a static quenching mechanism and Trp1237 and Tyr1323 residues were exposed to the solvent with the addition of xanthoangelol. Meanwhile, both experimental and theoretical studies display that hydrophilic forces play a key role in the formation of xanthoangelol-α2-macroglobulin complex, leading to a slight conformational change in α2-macroglobulin. In conclusion, our findings suggest that xanthoangelol, which has a high binding affinity for a plasma carrier protein, may inhibit the viability of HCC by inducing apoptosis and ER stress.

Hepatocellular carcinoma (HCC) is a major concern for public health. Fatty liver disease, related to alcohol misuse or metabolic syndrome, has become the leading cause of chronic liver disease and HCC. The strong association between type 2 diabetes mellitus and HCC can be partly attributed to the development of metabolic dysfunction-associated steatotic liver disease (MASLD). There is a strong interest in strategies that may mitigate HCC risk and reduce HCC incidence in this growing population of at-risk individuals. In this review, we describe the pathogenesis of HCC in patients with MASLD and discuss potential emerging pharmacological and lifestyle interventions for MASLD-related HCC. HCC risk has been observed to be lower with healthy lifestyle behaviors, such as healthy dietary patterns (eg, high consumption of vegetables, whole grains, fish and poultry, yogurt, and olive oil, and low consumption of red and processed meats and dietary sugar) and increased physical activity. Selecting an appropriate pharmacologic approach for individuals with MASLD may also decrease the occurrence of HCC. Metformin, PPAR activators, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, aspirin, and statins have all shown promise to reduce the risk of HCC, although guidelines do not recommend their use for the sole purpose of chemoprevention at this time, given a dearth of data defining their risk-benefit ratio.

The Liver Imaging Reporting and Data System (LI-RADS) does not consider factors extrinsic to the observation of interest, such as concurrent LR-5 observations.

To evaluate whether the presence of a concurrent LR-5 observation is associated with a difference in the probability that LR-3 or LR-4 observations represent hepatocellular carcinoma (HCC) through an individual participant data (IPD) meta-analysis.

Multiple databases were searched from 1/2014 to 2/2023 for studies evaluating the diagnostic accuracy of CT/MRI for HCC using LI-RADS v2014/2017/2018. The search strategy, study selection, and data collection process can be found at https://osf.io/rpg8x . Using a generalized linear mixed model (GLMM), IPD were pooled across studies and modeled simultaneously with a one-stage meta-analysis approach to estimate positive predictive value (PPV) of LR-3 and LR-4 observations without and with concurrent LR-5 for the diagnosis of HCC. Risk of bias was assessed using a composite reference standard and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2).

Twenty-nine studies comprising 2591 observations in 1456 patients (mean age 59 years, 1083 [74%] male) were included. 587/1960 (29.9%) LR-3 observations in 1009 patients had concurrent LR-5. The PPV for LR-3 observations with concurrent LR-5 was not significantly different from the PPV without LR-5 (45.4% vs 37.1%, p = 0.63). 264/631 (41.8%) LR-4 observations in 447 patients had concurrent LR-5. The PPV for LR-4 observations with concurrent LR-5 was not significantly different from LR-4 observations without concurrent LR-5 (88.6% vs 69.5%, p = 0.08). A sensitivity analysis for low-risk of bias studies (n = 9) did not differ from the primary analysis.

The presence of concurrent LR-5 was not significantly associated with differences in PPV for HCC in LR-3 or LR-4 observations, supporting the current LI-RADS paradigm, wherein the presence of synchronous LR-5 may not alter the categorization of LR-3 and LR-4 observations.

Annually, approximately 3.5 % of the world's population dies of cirrhosis or liver cancer, and the burden of liver disease is steadily expanding owing to multiple factors such as alcohol consumption, irrational diets, viral transmission, and exposure to drugs and toxins. However, the lack of effective therapies and the adverse effects of some medications remain a threat to the management of liver disease. Recently, immunometabolism, as an emerging discipline, appears to be the focus of unprecedented research. As a natural metabolite that regulates cellular functions, itaconate is a crucial bridge connecting metabolism and immune response. Remodeling immune function through metabolic modulation may be a promising alternative for disease intervention strategies. In this review, we first briefly describe the historical origin of itaconate and the development of its derivatives. This was followed by a review of the molecular mechanisms by which itaconate regulated immune-metabolic responses. Furthermore, we analyzed the effects of itaconate regulation on immune cells of the hepatic system. Finally, we summarized the experimental evidence for itaconate and its derivatives in the therapeutic application of liver diseases. Itaconate is potentially an invaluable component of emerging therapeutic strategies for liver disease.

The therapeutic efficacy of irreversible electroporation (IRE) for treating subcapsular hepatocellular carcinoma (HCC) remains under-explored. The current study aimed to compare IRE and radiofrequency ablation (RFA) outcomes in an HCC patient group.

In this retrospective cohort study, we analyzed 213 patients with subcapsular HCC who met the Milan criteria and underwent either IRE (n = 80) or RFA (n = 133). We assessed local tumor progression (LTP), recurrence-free survival (RFS), overall survival (OS), and complications rates, using inverse probability of treatment weighting (IPTW).

After a median follow-up of 22 months, patients in the IRE group showed significantly lower LTP rates (1-year: 6.2% [95% CI: 2.1-14.0%], 2-year: 8.8% [95% CI: 3.6-17.2%] vs. RFA 18.0% [95% CI: 11.9-25.6%], 21.1% [95% CI: 14.5-29.0%]; P = 0.008) and higher RFS rates (1-year: 75.0% [95% CI: 64.1-84.0%], 2-year: 67.5% [95% CI: 56.1-77.6%] vs. RFA 60.9% [95% CI: 52.1-69.2%], 51.9% [95% CI: 43.1-60.6%]; P = 0.003). However, 2-year OS remained comparable across groups (IRE 100% [95.5-100%] vs. RFA 99.1% [95.9-100%]; P = 0.990). IPTW-adjusted analyses confirmed these findings. We determined that treatment modality was an independent influencing factor for LTP (RFA vs. IRE HR [95% CI]: 2.46 [1.05, 5.74], P = 0.037) and RFS (RFA vs. IRE HR [95% CI]: 1.62 [1.01, 2.61], P = 0.046). However, the complication rate (6.3% vs. 9.8%) and median hospital stay (3 vs. 3 days) were similar across groups (both P > 0.05).

For patients with subcapsular HCC meeting the Milan criteria, IRE demonstrated significantly improved LTP and RFS compared to RFA. These results may suggest that IRE is a viable therapeutic alternative for this tumor subtype.

The high heterogeneity of hepatocellular carcinoma (HCC) poses challenges for precision treatment strategies. This study aims to use multi-omics methodologies to better understand its pathogenesis and discover biomarkers.

Quantitative proteomics was used to investigate hepatocellular carcinoma tissues (HCT) and their corresponding adjacent non-tumor tissues (DNT), obtained from six HCC patients. Untargeted metabolomics was applied to analyze the metabolic profiles of HCT and DNT of ten HCC patients. Statistical analyses, such as the Student's t-test, were performed to identify differentially expressed proteins (DEPs) and metabolites (DEMs) between the two groups. The functions and metabolic pathways involving DEPs and DEMs were annotated and enriched using the gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) databases. Bioinformatics methods were then utilized to analyze consistency between proteomics and metabolomics results, leading to identification of potential biomarkers along with key altered pathways associated with HCC.

This study identified 1556 DEPs between HCT and DNT samples. These DEPs were primarily enriched in crucial biological pathways such as amino acid degradation, fatty acid metabolism, and DNA replication. Subsequently, the analysis of metabolomics identified 500 DEMs that mainly participated in glycerophospholipid metabolism, the phospholipase D signaling pathway, and choline metabolism related to cancer. Integrated analysis of proteomics and metabolomics data unveiled significant dysfunctions in bile secretion, multiple amino acid and fatty acid metabolic pathways among HCC patients. Further investigation revealed that five proteins (PTP4A3, B4GALT5, GAB1, ME2, and PKM) along with seven metabolites (PI(6 keto-PGF1alpha/16:0), 13, 16, 19-docosatrienoic acid, PA(18:2(9Z, 12Z)/20:1(11Z)), Citric Acid, PG(20:3(6, 8, 11)-OH(5)/18:2(9Z, 12Z)), Spermidine, and N2-Acetylornithine) exhibited excellent diagnostic efficiency for HCC and could serve as its potential biomarkers.

Our integrated proteome and metabolome analysis revealed 10 key HCC-related pathways and proposed 12 potential biomarkers, which may enhance our understanding of HCC pathophysiology and be helpful in facilitating early diagnosis and treatment strategies.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The prognostic significance of the neutrophil-to-lymphocyte ratio (NLR) in HCC patients has been extensively studied; however, the prognostic value of NLR in HCC patients undergoing curative treatment remains unclear.

This systematic review and meta-analysis aimed to comprehensively evaluate the precise significance of preoperative and postoperative NLR in predicting the prognosis of HCC patients receiving curative treatment.

We conducted a comprehensive search of the PubMed, Cochrane Library, Embase, and Web of Science databases from inception to August 2024. Studies that included univariate and multivariate analyses evaluating the association between NLR and survival outcomes in HCC patients undergoing resection, transplantation, or ablation were included. The prognostic value of NLR in HCC patients receiving curative treatment was analyzed by calculating pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CIs).

A total of 43 studies involving 9,952 patients were included. Meta-analysis revealed that higher NLR was significantly associated with worse overall survival (OS) (HR = 1.55, 95% CI = 1.39-1.75, P < 0.001), recurrence-free survival (RFS) (HR = 1.77, 95% CI = 1.49-2.10, P < 0.001), and disease-free survival (DFS) (HR = 1.42, 95% CI = 1.25-1.63, P < 0.001) in HCC patients undergoing curative treatment. Subgroup analysis demonstrated a significant association between NLR and poor OS, independent of geographic region, type of survival analysis, preoperative or postoperative measurement, treatment modality, or NLR cutoff value. Publication bias and sensitivity analyses confirmed the robustness of these findings.

Elevated NLR is significantly associated with poorer OS, RFS, and DFS in HCC patients receiving curative treatment. Future research should focus on validating the optimal NLR threshold and exploring its predictive ability in different clinical settings.

This study aimed to investigate the expression of BEND3 in hepatocellular carcinoma (HCC), its correlation with clinical characteristics, and its functional and mechanistic impacts on HCC progression.

Bioinformatics analyses identified BEND3 as highly expressed in HCC and associated with poor clinical prognosis, which was further validated using qRT-PCR, western blotting and immunohistochemistry. Stable BEND3-overexpressing and silenced cell lines were constructed to evaluate its functional effects. CCK-8 and colony formation assays assessed its influence on cell proliferation, while wound healing and Transwell assays evaluated its role in migration and invasion. WB and immunofluorescence were employed to analyze the effects of BEND3 on epithelial-mesenchymal transition (EMT) and the PI3K/AKT/mTOR signaling pathway.

Public database analysis, alongside qRT-PCR, western blotting, and immunohistochemical, confirmed that BEND3 expression is significantly elevated in HCC tissues compared to normal liver tissues and is closely associated with poor prognosis. Functional assays demonstrated that BEND3 promotes HCC cell proliferation, migration, and invasion. Mechanistic studies revealed that BEND3 drives HCC progression by inducing EMT and activating the PI3K/AKT/mTOR signaling pathway.

BEND3 is highly expressed in HCC and strongly correlates with poor clinical outcomes. Functional and mechanistic analyses indicate that BEND3 enhances HCC progression by promoting proliferation, migration and invasion via EMT induction and PI3K/AKT/mTOR pathway activation.

Paeoniae Radix Alba (the root of Paeonia lactiflora Pall.) is a well-known Chinese herb medicine used for alleviating depression and anxiety. Paeoniflorin (PF), an active ingredient of Paeoniae Radix Alba, is usually used in emotion and inflammation-related diseases. In recent years, some studies showed that PF may also possess anti-tumor potential.

This study aimed to explore the effects of PF on chronic restraint stress (CRS)-induced hepatocellular carcinoma (HCC) progression and elucidate the potential molecular mechanisms.

ICR male mice bearing H22-Luc orthotopic transplant tumors were subjected to CRS and administrated with PF. To identify the direct target of PF, network pharmacology, RNA sequencing, and molecular docking analyses were employed. CCK8, Western blotting and qRT-PCR assays were performed to explore the molecular mechanisms of PF.

PF mitigated CRS-induced depression-like behaviors in tumor-bearing mice and suppressed the growth of orthotopically transplanted tumors. PF also decreased the number of c-fos positive neurons in the paraventricular nucleus of hypothalamus in CRS-exposed mice and lowered the serum norepinephrine (NE) level. NE treatment promoted the proliferation and αSMA production of hepatic stellate cells (HSCs), but did not alter the viability and migration of HCC cells. Furthermore, the conditional medium (CM) from NE-treated HSCs enhanced the proliferation and migration of HCC cells. PF not only inhibited NE-induced activation of HSCs, also reduced HSCs-CM induced viability and migration of HCC cells. Network pharmacology and RNA sequencing showed SRC was a potential target of PF in HSCs, which was further validated by molecular docking and cellular thermal shift assay. NE treatment upregulated the phosphorylation of SRC, AKT and ERK1/2 in HSCs, which was inhibited by PF.

The findings of this study support that PF could ameliorate CRS-induced HCC progression by inhibiting CRS-induced HSCs activation through SRC/AKT/ERK signaling pathway. Our work may provide a new prospect for PF in the treatment of HCC with comorbid psychological stress.

In recent years, several global phase III trials have shown that combinations of immune checkpoint inhibitors (ICIs) offer superior efficacy and survival compared to multi-kinase inhibitors, establishing them as the gold standard for treating patients with advanced hepatocellular carcinoma (HCC). This success has led to investigations into expanding the use of immunotherapy into various other settings and populations, including neoadjuvant and adjuvant therapies, patients with decompensated liver function and those awaiting liver transplantation. Despite its proven efficacy, a significant number of patients still develop resistance to immunotherapy, highlighting the need for innovative strategies to address this challenge. Approaches aimed at enhancing tumour immunogenicity, such as combining immunotherapy with transarterial chemoembolization or radiation therapies, show significant promise. Additionally, novel immunotherapeutics - such as triplet therapy, bispecific antibodies, adoptive T-cell therapy and cancer vaccines - are in early development for HCC. These agents have demonstrated potential for synergistic effects with existing ICIs, with initial studies yielding positive outcomes. In this review, we offer our future perspective on immunotherapy, emphasizing emerging indications, novel combination strategies and the development of new immunotherapeutic agents. Overall, the future of immunotherapy in HCC is brimming with extraordinary potential, set to transform the treatment landscape and redefine the possibilities for managing this challenging disease.

Hepatocellular carcinoma (HCC) is a prevalent and fatal tumor globally, characterized by a complex pathogenesis and poor prognosis. Despite significant advancements in the application of immune checkpoint inhibitors (ICIs) for cancer treatment, the efficacy of immunotherapy in HCC remains suboptimal. PSMD2, a crucial regulator of the ubiquitin-proteasome system, has attracted increasing attention for its involvement in various cancers; however, its functions and mechanisms in HCC are still poorly understood. This study aims to investigate the expression of PSMD2 in HCC, its association with prognosis, and its interaction with immune checkpoints, thus establishing a foundation for further exploration of its role in immune evasion in HCC. We analyzed the expression levels of PSMD2 in HCC and adjacent normal tissues utilizing the GEPIA and TIMER databases. Cox regression analysis was performed using R software to evaluate the relationship between PSMD2 expression and prognosis. Furthermore, we assessed the correlation between PSMD2 and immune cell infiltration, as well as immune checkpoints, including PD1, PD-L1, and CTLA-4, using R tools. Additionally, we examined the association between PSMD2 expression and immune therapy response through Tumor Immune Dysfunction and Exclusion (TIDE) analysis. Finally, we constructed a protein-protein interaction (PPI) network using the STRING database and Cytoscape software, followed by Gene Set Enrichment Analysis (GSEA). PSMD2 was significantly overexpressed in HCC and was closely correlated with poor prognosis (HR = 1.61, P = 2.0e-4). Immune infiltration analysis demonstrated that PSMD2 was positively correlated with several immune checkpoint genes, including PD1, PD-L1, and CTLA-4, as well as various immune cell types. TIDE analysis indicated that elevated PSMD2 expression was significantly associated with increased immune evasion potential and a poor response to immunotherapy. Furthermore, GSEA enrichment analysis revealed that PSMD2 is primarily enriched in the p53 signaling pathway, the ubiquitin-mediated proteolysis pathway, and other cancer-related pathways. The elevated expression of PSMD2 in HCC is not only correlated with poor prognosis but may also play a role in immune evasion by modulating tumor immunity, thereby affecting patient responses to immunotherapy. Consequently, PSMD2 presents a promising novel therapeutic target and potential biomarker for immunotherapy in HCC.

Hepatocellular carcinoma (HCC) is the most prevalent malignancy in China, with liver resection recognized as the primary curative intervention. However, HCC patients face an elevated risk of recurrence, thereby significantly impacting prognosis.

This study aimed to assess the impact of adjuvant programmed cell death protein-1 (PD-1) inhibitors on survival outcomes in patients with HCC who are at high risk for postoperative recurrence following curative hepatectomy.

Among the 199 study participants, 77 received adjuvant PD-1 inhibitors. Propensity score matching (PSM) was used to balance baseline differences between patients who received adjuvant PD-1 inhibitors and those who did not. Assessment of overall survival (OS) and recurrence-free survival (RFS) was conducted using Kaplan-Meier curves, while Cox regression analysis was employed to identify prognostic factors influencing survival.

After PSM, the 1-year and 2-year RFS were 87.1% and 74.2% in the PD-1 inhibitors group and 44.6% and 37.8% in non-PD-1 inhibitors group (p < 0.001). The 1-year and 2-year OS were 98.5% and 95.7% in the PD-1 inhibitors group compared with 90.7% and 77.0% in non-PD-1 inhibitors group (p = 0.004). Multivariable analyses demonstrated that the use of adjuvant PD-1 inhibitors was significantly associated with improved RFS and OS. Subgroup analysis indicated that adjuvant PD-1 inhibitors group achieved longer RFS than the non-PD-1 inhibitors group in patients without adjuvant transarterial chemoembolization (TACE).

The administration of adjuvant PD-1 inhibitors may effectively reduce the risk of tumor recurrence and improve survival in HCC patients with high risk of recurrence after curative hepatectomy.

Despite advances in surgical treatment, high recurrence after surgery remains a challenge for patients with hepatocellular carcinoma (HCC). This study aimed to investigate the association between compliance to regular follow-up and long-term oncological outcomes among patients undergoing curative resection for HCC.

This multicenter study included patients who underwent curative resection for early-stage HCC between January 2012 and December 2021 at 12 liver surgery centers. Patients were stratified into a regular follow-up group (follow-up every 2-3 months for the first 2 years and every 3-6 months thereafter) and an irregular/no follow-up group. Overall survival (OS), time to recurrence (TTR), and post-recurrence survival (PRS) were compared between the two groups.

Among 1544 patients, 786 (50.9 %) underwent regular follow-up during postoperative follow-up. The regular follow-up group had better OS (median: 113.4 vs. 94.5 months, P = 0.010) and PRS (median: 37.9 vs. 16.3 months, P < 0.001) than the irregular/no follow-up group, although TTR was comparable (median: 61.4 vs. 66.2 months, P = 0.161). Furthermore, patients in the regular follow-up group had a lower incidence of tumor beyond the Milan criteria at recurrence (41.6 % vs. 50.4 %, P = 0.013) and were more likely to receive curative treatments for recurrence (56.1 % vs. 49.3 %, P = 0.061). On multivariate analysis, compliance to regular follow-up was an independent factor associated with better OS [hazard ratio (HR) = 0.777, 95 % confidence interval (CI): 0.663-0.910, P = 0.002] and PRS (HR = 0.523, 95 % CI: 0.428-0.638, P < 0.001).

Compliance to regular follow-up improved OS and PRS after curative resection for HCC, highlighting the importance of postoperative regular follow-up for early detection of recurrence and timely intervention.

Leukotriene A4 hydrolase (LTA4H), an inflammatory mediator, has garnered attention for its role in the development of chronic lung diseases and various cancers. Our study highlights the protective role of LTA4H in hepatocellular carcinoma (HCC) occurrence and progression. LTA4H is downregulated in clinical and mouse HCC tumors. LTA4H deficiency exacerbates hepatocyte damage by restraining JNK activation and promotes CD206+ macrophage polarization through the upregulation of LTBP1 expression and downstream transforming growth factor β (TGF-β) secretion and activation. Mechanistically, LTA4H induces heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) phosphorylation, enhancing their interaction and leading to the functional inhibition of HNRNPA1 in regulating Ltbp1 mRNA maturation and processing in the nucleus. LTA4H-deficient patients exhibit poor prognosis and immunotherapy resistance. Combination therapy targeting TGF-β and PD-1 significantly improves the immunotherapy resistance of LTA4H-knockout Hepa1-6 tumors. Our findings reveal the previously unreported role of LTA4H in regulating the tumor microenvironment and provide insights into potential diagnostic and therapeutic strategies for patients with LTA4H-deficient HCC.

Baseline viral replication activity influences the risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B virus (HBV) infection.

To evaluate the impact of baseline viral replication activity on recurrence in HBV-related HCC after curative resection.

A multinational retrospective cohort of 2384 patients with very early or early-stage HBV-related HCC who consecutively underwent curative resection and received antiviral therapy (AVT) between 2010 and 2018 was analysed. Patients were categorised into ongoing-AVT (previously on AVT with viral suppression) and initiation-AVT (initiated AVT at the time of resection) groups. HCC recurrence was compared between these two groups based on baseline viral replication activity.

During a median follow-up of 4.9 years, 1188 (49.8%) patients developed recurrence. Multivariable analysis showed similar recurrence risk between the ongoing-AVT and initiation-AVT groups (HR, 1.09; 95% CI, 0.96-1.24). However, in cirrhotic patients, the initiation-AVT group had a higher recurrence risk than the ongoing-AVT group (HR, 1.22; 95% CI, 1.02-1.45) but not in non-cirrhotic patients (HR, 0.90; 95% CI, 0.73-1.09). Intriguingly, in the non-cirrhotic initiation-AVT group, a parabolic association was observed between baseline HBV DNA levels and the risk of recurrence, with those having 5-6 log10 IU/mL HBV DNA levels showing significantly higher recurrence risk compared to the ongoing-AVT group (HR, 1.78; 95% CI, 1.32-2.42).

The association between HBV replication activity and the risk of HCC recurrence varied depending on cirrhosis, providing important insights for optimising the timing of AVT and post-operative surveillance strategies.

SERPINI1 is a protein-coding gene, which has been reported to be related to malignancies, and the encoding protein is a secreted protein. Nevertheless, the specific effect of SERPINI1 on Hepatocellular carcinoma (HCC) remains unclear.

The expression level of SERPINI1 in cancers was detected by the Gene Expression Omnibus (GEO) database, the Gene Expression Profiling Interactive Analysis (GEPIA) database and the collected serum of HCC patients. The receiver operating characteristic (ROC) curve and area under curve (AUC) were used to evaluate the diagnostic effectiveness of serum SERPINI1 and the combination of AFP and SERPINI1 for HCC. The Kaplan-Meier (KM) survival was used to evaluate the prognostic capacity of SERPINI1 for HCC in GEPIA database. Furthermore, the correlations between clinicopathological characteristics and the level of serum SERPINI1 were analyzed. Besides, we detected the expression of SERPINI1 in HepG2 by qPCR and western blot, and confirmed the biological function of SERPINI1 through MTT, EdU, wound healing and transwell invasion assay.

The results indicated that the level of SERPINI1 was significantly increased in tissue and serum of HCC patients. ROC analysis displayed that SERPINI1 had a significantly diagnostic value for HCC, the combination of AFP and SERPINI1 gained the higher specificity and sensitivity. The KM survival curves indicated that patients with SERPINI1 overexpression had worse overall survival. Furthermore, we found the positive correlations between serum SERPINI1 level and some clinicopathological characteristics, such as tumor size, differentiation degrees and so on. In addition, in vitro experiments revealed that SERPINI1 could promote the proliferation and invasion of HCC.

Taken together, our study demonstrates that SERPINI1, which is highly expressed in HCC and closely related to cell proliferation and invasion, may serve as a novel biomarker for diagnosis and prognosis of HCC.

The global burden of liver cancer among adolescents and young adults (AYAs) has often been underestimated, despite significant shifts in its etiology. This study analyzes the disease burden of liver cancer in AYAs from 1990 to 2021 and forecasts trends up to 2040 using data from the Global Burden of Disease Study 2021. Our goal is to provide insights that can inform resource allocation and policy planning.

Incidence, mortality, and disability-adjusted life years (DALYs) data were extracted and estimated annual percentage changes calculated to assess trends. Correlation between age-standardized rates and sociodemographic index (SDI) was analyzed using Spearman correlation, and future trends were predicted using the Bayesian age-period-cohort model.

Globally, there were 24,348 new liver cancer cases and 19,270 deaths among AYAs in 2021, with decreases in age-standardized rates for incidence, mortality, and DALYs from 1990 to 2021. East Asia bears the highest burden, with males experiencing significantly higher rates than females. The burden increases with age, peaking at 35-39 years. Higher SDI is associated with lower incidence, mortality, and DALYs. While HBV remains the leading cause, NASH is the fastest-growing contributor to liver cancer incidence and mortality. Projections indicate a continued decline in liver cancer burden among AYAs, though female cases are expected to rise.

Despite a gradual decline in liver cancer burden among AYAs, NASH is emerging as a significant and rising cause of incidence and mortality. Regional and gender disparities persist, highlighting the need for tailored prevention and healthcare strategies to alleviate the liver cancer AYA's burden globally.

Hepatocellular carcinoma (HCC) is an exceedingly aggressive form of cancer that often carries a poor prognosis, especially when it is complicated by the presence of microvascular invasion (MVI). Identifying patients at high risk of MVI is crucial for personalized treatment strategies. Utilizing the single-cell RNA-sequencing dataset (GSE242889) of HCC, we identified malignant cell subtypes associated with microvascular invasion (MVI), in conjunction with the TCGA dataset, selected a set of MVI-related genes (MRGs). We developed an optimal prognostic model comprising 11 genes (NOP16, YIPF1, HMMR, NDC80, DYNLL1, CDC34, NLN, KHDRBS3, MED8, SLC35G2, RAB3B) based on MVI-related signature genes by integrating single-cell transcriptomic analysis with 101 machine learning algorithms. This model is meticulously crafted to forecast the prognosis of individuals afflicted with hepatocellular carcinoma (HCC). Additionally, we affirmed the predictive precision and superiority of our model through a meta-analysis against existing HCC models. Furthermore, we explored the differences between high- and low-risk groups through mutation and immune infiltration analyses. Lastly, we investigated immunotherapy responses and drug sensitivities between risk groups, providing novel therapeutic insights for liver cancer.

Protein kinase C delta (PKCδ) is a leaderless protein generally localized in the cytoplasm and nucleus; however, its extracellular unconventional protein secretion occurs exclusively in hepatocellular carcinoma (HCC) cells (but not in normal and non-cancerous hepatocytes or other gastrointestinal cancer cells) via an autophagy mechanism, despite the lack of a secretory signal. Therefore, PKCδ is detectable in the peripheral blood of HCC patients. Serum PKCδ indicates cancer-related unconventional protein secretion of an inactive form of cytosolic PKCδ and can be a unique biomarker independent of conventional markers. To examine the specificity of serum PKCδ for HCC, its levels and positivity rates were compared between 226 HCC and 108 gastrointestinal cancer patients. Furthermore, we focused on patients with malignant or benign intrahepatic tumors (17 intrahepatic cholangiocarcinoma, 42 liver metastases, and 6 focal nodular hyperplasia). A sandwich enzyme-linked immunosorbent assay was used to measure serum PKCδ levels; the optimal cutoff value was set to 57.7 ng/mL. HCC patients had significantly higher PKCδ levels and positivity rates than gastrointestinal cancer patients (median, 51.1 vs. 34.6 ng/mL; 39.8 % vs. 4.6 %; P < 0.001 for both). Thus, the specificity was 95.4 %. Focusing on intrahepatic tumors, 2 (4.8 %) of 42 gastrointestinal cancer patients with liver metastasis were positive for PKCδ. Notably, all patients with intrahepatic cholangiocarcinoma and focal nodular hyperplasia were negative for PKCδ, irrespective of their intrahepatic tumors being malignant or benign. Serum PKCδ is an extracellularly secreted protein specific for HCC that can be a novel diagnostic biomarker because it distinguishes HCC from other gastrointestinal cancers and intrahepatic non-HCC tumors.

Despite the pivotal role of CTLs in antitumor immunity, a substantial proportion of CTL-rich patients with hepatocellular carcinoma (HCC) experience early relapse or immunotherapy resistance. However, spatial immune variations impacting the heterogeneous clinical outcomes of CTL-rich HCCs remain poorly understood. In this study, we compared the single-cell and spatial landscapes of 20 CTL-rich HCCs with distinct prognoses using multiplexed in situ staining and validated the prognostic value of myeloid spatial patterns in a cohort of 386 patients. Random forest and Cox regression models identified macrophage aggregation as a distinctive spatial pattern characterizing a subset of CTL-rich HCCs with an immunosuppressive microenvironment and poor prognosis. Integrated analysis of single-cell and spatial transcriptomics, combined with in situ staining validation, revealed that spatial aggregation enhanced protumoral macrophage reprogramming in HCCs, marked by lipid metabolism orientation, M2-like polarization, and increased adjacent CTL exhaustion. This spatial effect on macrophage reprogramming was replicated in HCC-conditioned human macrophage cultures, which showed an enhanced capability to suppress CTLs. Notably, increased macrophage aggregation was associated with higher response rates to anti-PD-1 immunotherapy. These findings suggest that the spatial distribution of macrophages is a biomarker of their functional diversities and microenvironment status, which holds prognostic and therapeutic implications.

Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) is an oncofetal protein, is strongly associated with tumor initiation and progression due to its upregulation. However, the regulatory mechanisms driving IGF2BP3 upregulation and its contribution to the development and progression in hepatocellular carcinoma (HCC) remain unclear. In this study, we demonstrated that IGF2BP3 is re-expressed in HCC mouse models, with elevated levels correlating with a poor prognosis in patients with HCC. Our data revealed that histone acetylation at the IGF2BP3 promoter region drives transcription activation of IGF2BP3 in primary hepatocytes. Notably, histone acetylation and transcriptional reactivation of IGF2BP3 were observed in human HCC tissues as well. Mechanistically, IGF2BP3 knockdown modulated the cell cycle and cell proliferation by limiting G1/S phase transition, which is dependent on cyclin D1. We further showed that IGF2BP3 maintains CCND1 mRNA stability by directly interacting with its 3'UTR. Importantly, IGF2BP3 recruits the RNA stabilizer PABPC1 to potentiate CCND1 mRNA stability. These two proteins synergistically protect CCND1 mRNA from degradation. Furthermore, IGF2BP3-depleted HCC cells were unable to form tumors in the xenograft model. High IGF2BP3 and CCND1 levels predicted poor outcomes in patients. Collectively, our findings highlight the pivotal role of the IGF2BP3/cyclin D1 axis and reveal a new regulatory mechanism for IGF2BP3 re-expression via transcriptional activation during hepatocarcinogenesis. These results indicate that the IGF2BP3/CCND1 axis is a promising prognostic biomarker and potential therapeutic target for HCC.

Our study aimed to explore whether hepatitis B surface antigen (HBsAg) levels affected the role of nucleot(s)ide analog treatment (entecavir [ETV] and tenofovir disoproxil fumarate [TDF]) in improving the prognosis of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after liver resection.

A total of 865 patients with HBV-related HCC after hepatectomy treated with TDF or ETV were included in our study. Patients were divided into the high HBsAg cohort (n = 681) and the low HBsAg cohort (n = 184). Propensity score matching (PSM) analysis was used to reduce the impact of potential confounding factors. Kaplan-Meier method and competing risk analysis were used to compare the survival outcomes.

In the high HBsAg cohort, patients in the TDF group had better recurrence-free survival (RFS) and overall survival (OS) compared with patients in the ETV group both before (RFS: P < 0.001; OS: P < 0.001) and after (RFS: P = 0.005; OS: P = 0.035) PSM. TDF treatment was a favorable factor independently associated with RFS (hazard ratio: 0.58, 95% confidence interval: 0.45-0.75, P < 0.001) and OS (hazard ratio: 0.43, 95% confidence interval: 0.28-0.66, P < 0.001). In the low HBsAg cohort, no difference was observed in RFS and OS between the TDF group and the ETV group both before (RFS: P = 0.140; OS: P = 0.640) and after (RFS: P = 0.480; OS: P = 0.920) PSM. TDF treatment remained superiority after controlling for competing events by competing risk analysis in the high HBsAg cohort.

TDF treatment was superior to ETV treatment in improving RFS and OS of HBV-related HCC patients with high HBsAg level after liver resection. Even after controlling for survival competing events, the advantage of TDF treatment remained. Our findings may better help clinicians to assign individualized antiviral regimens to patients with HBV-related HCC after liver resection.

Yes-associated protein (YAP) plays a central role in the Hippo pathway, primarily governing cell proliferation, differentiation, and apoptosis. Its significance extends to tumorigenesis and inflammatory conditions, impacting disease initiation and progression. Given the increasing relevance of YAP in inflammatory disorders and cancer, this study aims to elucidate its pathological regulatory functions in these contexts. Specifically, we aim to investigate the involvement and molecular mechanisms of YAP in various inflammatory diseases and cancers. We particularly focus on how YAP activation, whether through Hippo-dependent or independent pathways, triggers the release of inflammation and inflammatory mediators in respiratory, cardiovascular, and digestive inflammatory conditions. In cancer, YAP not only promotes tumor cell proliferation and differentiation but also modulates the tumor immune microenvironment, thereby fostering tumor metastasis and progression. Additionally, we provide an overview of current YAP-targeted therapies. By emphasizing YAP's role in inflammatory diseases and cancer, this study aims to enhance our understanding of the protein's pivotal involvement in disease processes, elucidate the intricate pathological mechanisms of related diseases, and contribute to future drug development strategies targeting YAP.

Postoperative complications are potential factors influencing the prognosis of patients with HCC combined with CSPH. This study aims to explore the risk factors affecting the occurrence of postoperative complications, investigate potential factors influencing long-term prognosis in these patients, and establish predictive models.

From April 2018 to December 2021, a total of 190 patients with HCC combined with CSPH who underwent curative liver resection in our hospital were included, comprising 69 cases in the complication group and 121 cases in the non-complication group. LASSO-Logistic regression was employed to identify risk factors influencing postoperative complications and establish a predictive model. LASSO-Cox regression was used to determine prognostic factors for long-term outcomes in patients with HCC combined with CSPH and establish a predictive model.

LASSO regression selected variables including ALBI grade, preoperative ascites, major hepatectomy, and portal vein occlusion time >15 ​min. These variables were incorporated into logistic regression (P ​< ​0.05) to establish a nomogram for predicting postoperative complications, with a C-index of 0.723. Results from the multivariable Cox regression analysis showed that postoperative complications, maximum tumor diameter, and microvascular invasion were risk factors for recurrence, while postoperative complications, maximum tumor diameter, microvascular invasion, and prealbumin were risk factors for overall survival. The C-index values for the respective nomograms were 0.635 and 0.734. The calibration curves and ROC curves demonstrated good performance for all three nomograms.

The three nomograms achieved optimal predictive performance for postoperative complications, recurrence, and overall survival in patients with HCC combined with CSPH undergoing curative resection.

Cholangiocarcinomas are a highly heterogeneous group of malignancies that, despite recent progress in the understanding of their molecular pathogenesis and clinical management, continue to pose a major challenge to public health. The traditional view posits that cholangiocarcinomas derive from the neoplastic transformation of cholangiocytes lining the biliary tree. However, increasing genetic and experimental evidence has recently pointed to a more complex, and nuanced, scenario for the potential cell of origin of cholangiocarcinomas. Hepatocytes as well as hepatic stem/progenitor cells are being considered as additional potential sources, depending on microenvironmental contexts, including liver injury. The hypothesis of potentially diverse cells of origin for cholangiocarcinoma, albeit controversial, is certainly not surprising given the plasticity of the cells populating the liver as well as the existence of liver cancer subtypes with mixed histologic and molecular features. This review carefully examines the current pathologic, genomic, and experimental evidence supporting the existence of multiple cells of origin of liver and biliary tract cancers, with particular focus on cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma.

Patients with cirrhosis are at high risk for hepatocellular carcinoma (HCC), but few undergo guideline-recommended semi-annual screening. Randomized clinical trials (RCTs) demonstrate that mailed outreach can increase screening versus visit-based screening. We estimated the costs and cost-effectiveness of an outreach strategy versus usual care.

We built a 10-year Markov chain Monte Carlo microsimulation model to conduct a cost-effectiveness analysis comparing a mailed outreach program versus usual care for HCC screening in a cohort of 10,000 patients with cirrhosis. Model inputs were based on literature review (2005-current), and costs were based on inflation-adjusted estimates from Surveillance, Epidemiology, and End Results (SEER)-Medicare claims data. We conducted one-way sensitivity analyses for HCC incidence, outreach costs, efficacy of the outreach strategy to increase screening, and efficacy of curative (versus palliative) HCC treatments.

Mailed outreach was estimated to cost $32.45 per patient in the first year and $21.90 per patient in subsequent years. The outreach program increased the number of HCC patients detected at an early stage by 48.4% and increased quality-adjusted life years (QALYs) by 300. Cost savings from these increases offset the costs of mailed outreach. Mailed outreach remained cost-effective across a wide range of HCC incidence rates, outreach costs, efficacy of the outreach strategy to increase screening, and the efficacy of curative HCC treatments. Annual out-of-pocket patient costs in the outreach arm were low at $13 per year.

Mailed outreach to encourage HCC screening in patients with cirrhosis dominates usual care and should be considered for implementation in routine practice.

National Cancer Institute and Cancer Prevention Research Institute of Texas.

Hepatocellular carcinoma (HCC) is associated with a dismal prognosis, primarily due to its high rates of metastasis and recurrence. Metabolic reprogramming, specifically enhanced glycolysis, is a prominent feature of cancer progression. This study identifies ubiquitin-specific peptidase 27 X-linked (USP27) as a significant regulator of glycolysis in HCC. We demonstrate that USP27 stabilizes PFKFB3, a key glycolytic enzyme, through deubiquitination, thereby increasing glycolytic activity and facilitating tumor progression. Furthermore, we reveal that CTCF, a well-known transcription factor, directly binds to the USP27 promoter and upregulates its expression, thereby establishing a connection between transcriptional regulation and metabolic reprogramming in HCC. Knockdown of USP27 or CTCF in HCC cells considerably decreased glycolysis and proliferation, while overexpression had the opposite effect. In vivo studies confirmed that USP27 knockdown suppresses HCC growth and metastasis. Our findings establish the CTCF/USP27/PFKFB3 axis as a novel mechanism driving HCC progression through glycolysis, indicating that targeting this pathway could offer new therapeutic opportunities. These results provide valuable insights into the molecular mechanisms underlying HCC and emphasize the potential of targeting USP27-mediated metabolic pathways as a strategy for cancer treatment.

Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis.

Molecular (prognostic liver secretome signature with α-fetoprotein) and clinical (aMAP [age, male sex, albumin-bilirubin, and platelets] score) variable-based scores were integrated into PAaM (prognostic liver secretome signature with α-fetoprotein plus age, male sex, albumin-bilirubin, and platelets), which was subsequently validated in 2 phase 3 biomarker validation studies: the statewide Texas HCC Consortium and nationwide HCC Early Detection Strategy prospective cohorts, following the prospective specimen collection, retrospective blinded evaluation design. The associations between baseline PAaM and incident HCC were assessed using Fine-Gray regression, with overall death and liver transplantation as competing events.

Of 2156 patients with cirrhosis in the Texas HCC Consortium, PAaM identified 404 (19%) high-risk, 903 (42%) intermediate-risk, and 849 (39%) low-risk patients with annual HCC incidence rates of 5.3%, 2.7%, and 0.6%, respectively. Compared with low-risk patients, high- and intermediate-risk groups had sub-distribution hazard ratios for incident HCC of 7.51 (95% CI, 4.42-12.8) and 4.20 (95% CI, 2.52-7.01), respectively. Of 1328 patients with cirrhosis in the HCC early detection strategy, PAaM identified 201 high-risk (15%), 540 intermediate-risk (41%), and 587 low-risk (44%) patients, with annual HCC incidence rates of 6.2%, 1.8%, and 0.8%, respectively. High- and intermediate-risk groups were associated with sub-distribution hazard ratios for incident HCC of 6.54 (95% CI, 3.85-11.1) and 1.77 (95% CI, 1.02-3.08), respectively. Subgroup analysis showed robust risk stratification across HCC etiologies, including metabolic dysfunction-associated steatotic liver disease and cured hepatitis C infection.

PAaM enables accurate HCC risk stratification in patients with cirrhosis from contemporary etiologies.