Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic targets. P53 and DNA damage-regulated gene 1 (PDRG1) has emerged as an oncogene in multiple cancers, yet its role and regulatory mechanism in HCC remain unclear. Here, we demonstrated that PDRG1 expression was significantly upregulated in HCC tissues compared to normal liver, correlating with advanced tumor stage, higher grade, and poor patient survival. Functionally, PDRG1 knockdown suppressed HCC cell proliferation, migration, and invasion in vitro and inhibited tumor growth and lung metastasis in vivo, whereas PDRG1 overexpression exerted opposite effects. Mechanistically, PDRG1 activated Wnt/β-catenin signaling, elevating levels of β-catenin, c-Myc, and phosphorylated GSK-3β, and the oncogenic effects of PDRG1 were reversed by the Wnt pathway inhibitor XAV939. Furthermore, transcription factor Specificity Protein 1 (SP1) bound directly to the PDRG1 promoter at the E3 site (–1927 to–1917) and activated its transcription. The pro-tumor effects of SP1 were rescued by PDRG1 silencing, indicating that SP1 acts through PDRG1. Collectively, our study identifies SP1 as an upstream transcriptional activator of PDRG1 and defines the SP1/PDRG1/Wnt/β-catenin axis as a key regulatory pathway promoting HCC progression, suggesting its potential as a prognostic biomarker and therapeutic target.

Hepatocellular carcinoma (HCC) is a common malignancy and a leading cause of cancer-related mortality. Current guidelines and staging systems provide coarse categories, but often miss within-stage heterogeneity and the clinical context in electronic medical records (EMRs). We present HCC-STAR (Hepatocellular Carcinoma Staging, Treatment And pRognosis), a clinically aligned large language model that reads routine EMR narratives and jointly outputs risk score-based staging, ranked guideline-consistent treatments with evidence-based rationales, and individualized survival estimates. We curated about 30,000 HCC cases from SEER and expanded them into EMR-style narrative training data using a clinician-validated, prompt-based augmentation workflow. On this corpus, we developed a knowledge-aligned reasoning framework optimized with a step-verifiable composite reward, moving beyond text-level memorization of clinical guidelines. In a multi-center cohort of 6,668 patients from 12 hospitals in China, HCC-STAR achieved state-of-the-art performance in treatment recommendation and risk stratification compared with clinical guidelines and competitive models, including GPT-5 and Gemini-2.5 Pro. Hypothetical overall-survival analysis showed a median survival of 51 months under adherence to HCC-STAR recommendations, compared with 29 and 32 months under BCLC and CNLC. In clinician-centric evaluations, blinded hepatobiliary specialists rated HCC-STAR's reasoning and evidence-based justifications as trustworthy. The model surpassed resident and attending physicians in treatment accuracy and helped physicians make more accurate decisions faster when used as an assistant. These findings support HCC-STAR as a reliable and verifiable decision-support system for risk stratification and precision therapy in HCC.

Hepatocellular carcinoma (HCC), accounting for 75–85

BACKGROUND AND AIMS:The rising global incidence of cholangiocarcinoma (CCA) coincides with epidemics of type 2 diabetes (T2D) and chronic hepatitis B virus (HBV) infection. Although both are established independent risk factors, the shared molecular mechanisms by which they contribute to cholangiocarcinogenesis remain poorly understood. We hypothesized that T2D and HBV converge on a state of chronic metabolic inflammation ("metaflammation") that drives CCA progression through a conserved transcriptomic network. METHODS:We performed an integrative bioinformatics analysis of transcriptomic data from public repositories, including samples of CCA (TCGA-CHOL, n = 45; GSE107943, n = 163), T2D-affected liver (GSE23343, n = 20), and HBV-infected liver (GSE58208, n = 102). Acknowledging that the T2D and HBV datasets were derived from whole-liver tissue, whereas CCA originates in the biliary epithelium, we identified differentially expressed genes (DEGs) across conditions and defined a core gene set shared among them. Subsequent analyses included functional enrichment, construction of protein-protein interaction (PPI) networks, survival analysis, and protein validation. RESULTS:We identified a core metaflammation signature comprising 156 genes that were consistently dysregulated across T2D, HBV, and CCA. Pathway analysis revealed significant enrichment in PPAR signaling, cytokine-cytokine receptor interaction, PI3K-Akt, and TNF signaling pathways. Protein-protein interaction (PPI) network analysis identified IL6, TNF, AKT1, STAT3, and PPARG as the top hub genes. These hubs were functionally modularized into clusters associated with inflammatory signaling, metabolic regulation, and cell growth and survival. In the TCGA CCA cohort, high expression of IL6, TNF, AKT1, and STAT3 and low expression of PPARG correlated with advanced tumor stage and poorer overall survival (e.g., IL6: ρ = 0.42, p = 0.01). A metaflammation score derived from these hubs (weighted combination of the five genes) emerged as an independent prognostic factor (HR = 2.8, p < 0.001). Protein-level dysregulation of these hubs was confirmed via immunohistochemistry. CONCLUSIONS:This study defines a conserved metaflammation network that links T2D and HBV to CCA, identifying key hub genes and pathways. This signature provides a mechanistic explanation for epidemiological risks, serves as a novel prognostic tool, and offers a rationale for targeting metaflammation in prevention and therapy for high-risk populations.

ObjectiveThis study aimed to characterize molecular subtypes of Papillary thyroid carcinoma (PTC) and identify novel therapeutic targets and potential therapeutic compounds.MethodsWe performed integrative analysis of TCGA data, including consensus clustering, mutational profiling, copy number variation (CNV) analysis, functional enrichment (GO and GSEA), and immune microenvironment assessment (CIBERSORT). Validation utilized GEO datasets. The biological function of Plectin (PLEC) was investigated through expression analysis (TCGA, GEO, qRT-PCR and IHC), association with clinical parameters, and functional experiments such as siRNA knockdown or overexpression of PLEC in TPC-1 and B-CPAP cell lines assessing cell growth, proliferation, apoptosis, and migration both in vitro and in vivo. Drug candidates targeting PLEC were screened (DGIdb and DrugMap) and validated via molecular docking, dynamics simulations (RMSD, RMSF and Rg), and rescue experiments. Favorable biosafety was tested by ELISA kits and H&E staining.ResultsConsensus clustering revealed four stable molecular subtypes (A1-A4) with distinct mutational landscapes (e.g., prevalent BRAF mutations (59%), subtype-specific alterations in CAND1/PCDH11X (A1) and PTEN (A4)), CNV gains (e.g., A1: 2p16.1/19p13.3), and immune features (A3 enriched in immune pathways). PLEC is up-regulated in PTC tissues compared with non-tumor thyroid tissues and was associated with lymph node metastasis, histological type, and residual tumor status in TCGA-THCA. Knockdown of PLEC significantly suppressed PTC cell growth, proliferation, and migration while inducing apoptosis. Whereas PLEC overexpression partially reversed these phenotypes. Among FDA-approved drugs predicted to target PLEC, Troglitazone exhibited the lowest binding affinity (-7.5 kcal/mol). Troglitazone’s anti-tumor effects (inhibiting proliferation/migration, inducing apoptosis) were partially reversed by PLEC overexpression, suggesting that PLEC may participate in Troglitazone-associated anti-PTC effects.ConclusionThese findings identify PLEC as a candidate molecule associated with aggressive PTC phenotypes and provide preliminary evidence supporting its biological relevance, although larger independent cohorts are required to validate its clinical significance.

ABSTRACTImmunotherapy has revolutionized cancer treatment in recent years, yet non‐responsiveness of immunotherapy remains a challenge for cancer treatment. Therefore, the prediction method for potential clinical benefits of patients from immunotherapy is urgently needed. This study aims to develop an effective clinical practice assistance tool to evaluate the potential clinical benefits and therapy responsiveness of patients undergoing immunotherapy. We developed an immunotherapy resistance score (IRS), which performed well compared with conventional immunotherapy response indicators across different immunotherapy cohorts. Tumor microenvironment (TME) analysis showed that both immune and nonimmune features collectively impact immunotherapy responsiveness. Thus, IRS was constructed based on the TME features using machine learning approaches. The clinical application potential of IRS has been demonstrated in our in‐house Harbin Medical University (HMU) cohort and an external validation cohort. Furthermore, we analyzed the correlation between IRS and pathways related to cancer therapy targets to explore the application potential of IRS in comprehensive cancer therapy. In conclusion, IRS is a robust tool for predicting patient immunotherapy prognosis, which has great potential to promote precise clinical therapy.

Background and Aims: Cell cycle checkpoint-related genes (CCCRGs) are implicated in the development and progression of hepatocellular carcinoma (HCC). However, their precise roles and underlying mechanisms remain insufficiently characterized and require further investigation. This study aimed to explore the prognostic significance of CCCRGs in HCC, and to investigate the mechanism by which they promote the progression of HCC. Methods: HCC datasets from The Cancer Genome Atlas and International Cancer Genome Consortium were analyzed to identify hub genes. A prognostic model was constructed and validated using Kaplan-Meier analysis, nomogram, calibration curves, decision curve analysis, and receiver operating characteristic analysis. Immune infiltration patterns were assessed using single sample gene set enrichment analysis, while pathway activities were evaluated via gene set variation analysis. Single-cell RNA sequencing data from GSE149614 were analyzed with Seurat and CellChat to investigate cell-cell communication. Patientderived HCC specimens were examined through immunohistological evaluation, HCC cell lines were used for in vitro functional assays, and in vivo tumor growth was assessed through animal experiments. Results: CCCRGs showed significant associations with prognosis, malignant biological behavior, and immune responses in HCC. Centromere protein (CENP) I was identified as a critical hub gene that markedly promoted HCC proliferation, metastasis, and epithelial-mesenchymal transition, while inhibiting apoptosis. Mechanistically, CENPI suppressed YAP phosphorylation, enhancing its nuclear translocation and thereby driving malignant progression. Additionally, CENPI impaired immune effector cell infiltration, likely by disrupting tumor antigen presentation and chemokine-mediated CD8+ T cell chemotaxis, thereby promoting immune escape. Conclusions: This study underscores the prognostic significance of CCCRGs in HCC and identifies CENPI as a key driver of tumor progression through the Hippo pathway. Furthermore, it reveals CENPI's role in promoting immune escape, suggesting novel therapeutic targets for HCC treatment.

The cause and carcinogenesis of cholangiocarcinoma (CCA) remain unclear. In this study, we conducted a population-based case-control study in China to evaluate the effects of diabetes mellitus (DM), hepatitis B virus (HBV) infection, and other potential risk factors for cholangiocarcinoma (CCA). A hospital-based, case-control study was conducted, including 245 CCA patients (168 with extrahepatic cholangiocarcinoma (eCCA) and 77 with intrahepatic cholangiocarcinoma (iCCA), diagnosed at The Second Affiliated Hospital of Harbin Medical University in China between January 2019 and June 2024, along with 490 healthy controls matched in a 2:1 ratio. Conditional logistic regression and the synergism index were used to analyze risk factors for cholangiocarcinoma and their potential correlations. There was an association between DM, HBV infection, cholelithiasis, choledocholithiasis, hepatolithiasis, and thyroid diseases were significantly and positively correlated with CCA, with adjusted odds ratios (AOR = 1.53; 95

Epigenetic changes are heritable changes in gene expression without changes in the nucleotide sequence of genes. Epigenetic changes play an important role in the development of cancer and in the process of malignancy metastasis. Previous studies have shown that abnormal epigenetic changes can be used as biomarkers for disease status and disease prediction. The reversibility and controllability of epigenetic modification changes also provide new strategies for early disease prevention and treatment. In addition, corresponding drug development has also reached the clinical stage. In this paper, we will discuss the recent progress and application status of tumor epigenetic biomarkers from three perspectives: DNA methylation, non-coding RNA, and histone modification, in order to provide new opportunities for additional tumor research and applications.

The technology of three-dimensional (3D) printing emerged in the late 1970s and has since undergone considerable development to find numerous applications in mechanical engineering, industrial design, and biomedicine. In biomedical science, several studies have initially found that 3D printing technology can play an important role in the treatment of diseases in hepatopancreatobiliary surgery. For example, 3D printing technology has been applied to create detailed anatomical models of disease organs for preoperative personalized surgical strategies, surgical simulation, intraoperative navigation, medical training, and patient education. Moreover, cancer models have been created using 3D printing technology for the research and selection of chemotherapy drugs. With the aim to clarify the development and application of 3D printing technology in hepatopancreatobiliary surgery, we introduce seven common types of 3D printing technology and review the status of research and application of 3D printing technology in the field of hepatopancreatobiliary surgery.

BackgroundNon-alcoholic fatty liver disease (NAFLD), which includes simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), is a significant contributor to liver disease on a global scale. The change of immunity-related genes (IRGs) expression level leads to different immune infiltrations. However, the expression of IRGs and possible regulatory mechanisms involved in NAFLD remain unclear. The objective of our research is to investigate crucial genes linked to the development of NAFLD and the transition from SS to NASH.MethodsDataset GSE89632, which includes healthy controls, SS patients, and NASH patients, was obtained using the GEO database. To examine the correlation between sets of genes and clinical characteristics, we employed weighted gene co-expression network analysis (WGCNA) and differential expression analysis. Hub genes were extracted using a network of protein-protein interactions (PPI) and three different machine learning algorithms. To validate the findings, another dataset that is publicly accessible and mice that were subjected to a high-fat diet (HFD) or MCD diet were utilized. Furthermore, the ESTIMATE algorithm and ssGSEA were employed to investigate the immune landscape in the normal versus SS group and SS versus NASH group, additionally, the relationship between immune infiltration and the expression of hub genes was also examined.ResultsA total of 28 immune related key genes were selected. Most of these genes expressed reverse patterns in the initial and progressive stages of NAFLD. GO and KEGG analyses showed that they were focused on the cytokine related pathways and immune cell activation and chemotaxis. After screening by various algorithms, we obtained two hub genes, including JUN and CCL20. Validation of these findings was confirmed by analyzing gene expression patterns in both the validation dataset and the mouse model. Ultimately, two hub genes were discovered to have a significant correlation with the infiltration of immune cells.ConclusionWe proposed that there were dynamic changes in the expression levels of IRGs in different stages of NAFLD disease, which led to different immune landscapes in SS and NASH. The findings of our research could serve as a guide for the accurate management of various phases of NAFLD.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a notably poor prognosis. A large number of patients with PDAC develop metastases before they are diagnosed with metastatic pancreatic cancer (mPDAC). For mPDAC, FOLFIRINOX or gemcitabine plus nab-paclitaxel are the current first-line treatments. It is important to note, however, that many patients will fail chemotherapy because of drug resistance. Heterogeneous tumors and complex tumor microenvironments are key factors. As a result, clinical researchers are exploring a variety of alternative treatment modalities. Current understanding of the molecular signature and immune landscape of PDAC has motivated the emergence of different targeted and immune-based therapeutic approaches, some of which have shown promising results. The purpose of this review is to discuss the new targets and new drugs for mPDAC in terms of specific pathogenic factors such as metabolic vulnerability, DNA damage repair system, tumor microenvironment and immune system, in order to identify potential vulnerabilities in mPDAC patients and hopefully improve the prognosis of mPDAC patients.

Among primary liver cancers, hepatocellular carcinoma is the most common pathological type. Its onset is insidious, and most patients have no obvious discomfort in the early stage, so it is found late, and the opportunity for surgical radical treatment is lost, resulting in a poor prognosis. With the introduction of molecular-targeted drugs represented by sorafenib, patients with middle- and late-stage liver cancer have regained the light of day. However, their therapeutic efficacy is relatively low due to the limited target of drug action, toxic side effects, and other reasons. At this time, the emergence of immunotherapy represented by immune checkpoint inhibitors (ICIs) well breaks this embarrassing situation, which mainly achieves the anti-tumor purpose by improving the tumor immune microenvironment. Currently, ICI monotherapy, as well as combination therapy, has been widely used in the clinic, further prolonging the survival of patients with advanced hepatocellular carcinoma. This article reviews the development of monotherapy and combination therapy for ICIs in advanced hepatocellular carcinoma and the latest research progress.

Hepatocellular carcinoma (HCC) is a malignant tumor that arises from hepatocytes. Multiple signaling pathways play a regulatory role in the occurrence and development of HCC, with the Wnt signaling pathway being one of the primary regulatory pathways. In normal hepatocytes, the Wnt signaling pathway maintains cell regeneration and organ development. However, when aberrant activated, the Wnt pathway is closely associated with invasion, cancer stem cells(CSCs), drug resistance, and immune evasion in HCC. Among these factors, the development of drug resistance is one of the most important factors affecting the efficacy of HCC treatment. These mechanisms form the basis for tumor cell adaptation and evolution within the body, enabling continuous changes in tumor cells, resistance to drugs and immune system attacks, leading to metastasis and recurrence. In recent years, there have been numerous new discoveries regarding these mechanisms. An increasing number of drugs targeting the Wnt signaling pathway have been developed, with some already entering clinical trials. Therefore, this review encompasses the latest research on the role of the Wnt signaling pathway in the onset and progression of HCC, as well as advancements in its therapeutic strategies.

Cholangiocarcinoma（CCA） is a malignant tumor originating from the biliary system. Although surgery is the recognized radical treatment for CCA, the treatment results are not satisfactory due to the special anatomical characteristics of the biliary system and the high aggressiveness of the disease. Drug therapy has become an option for patients with advanced CCA to achieve a better outcome. Drug treatment mainly includes chemotherapy, targeted therapy and immunotherapy. At present, two important therapeutic targets, the fibroblast growth factor receptor and isocitrate dehydrogenase 1, have been found in studies, and the targeted therapeutic drugs against them generally showed positive effects in clinical trials. Although CCA generally expresses PD-1/PD-L1, it is not sensitive to immune checkpoint inhibitors, and the efficacy can be improved by combining other immunotherapy drugs. Traditional chemotherapy has the most stable efficacy for CCA compared with emerging targeted therapies and immunotherapies. The National Comprehensive Cancer Network guidelines recommend cisplatin plus gemcitabine as the first-line chemotherapy regimen for patients with advanced unresectable CCA or CCA presenting with metastatic symptoms. Recent advances in these drugs will significantly improve the survival benefits of CCA patients.

目前全球器官移植领域所面临的仍是供体短缺的主要问题.由于受体需求量和标准供体的数量的严重不平衡,外科医生们将目光转移到心脏死亡供体(DCD).相比于脑死亡供体(DBD),DCD面临的主要问题是经历更长的热缺血时间(WIT),以致患者术后并发症发生率增加,尤其是胆道并发症.受控心脏死亡供体(cDCD)是指在符合患者或家属意愿的情况下有计划地退出维持生命的治疗,在一段"无接触"时间后(通常为5 min),宣布患者大脑循环永久缺失,同时快速进行器官恢复.由于使用常规器官保存方法保存的DCD移植物的移植效果不尽如人意,近年来,常温灌注技术所展现出的优势在移植过程中愈发明显,逐渐引起外科医生和科学家们的关注.与活体肝移植以及DBD肝移植不同,DCD在宣布死亡前无法取出移植物.而在常温局部灌注(NRP)中,外科医生们能够在宣布死亡后阻断流向大脑的血液,并通过体外膜氧合启动器官的热灌注,在供体体内恢复供体肝脏的功能,使肝脏产生胆汁并清除乳酸.这一过程为供体肝脏离开供体和移植前的各项指标监测和优化提供宝贵时间.目前已有多项临床研究表明,NRP作为一种原位器官修复技术能够使cDCD供体肝脏的移植效果与DBD供体相近.另外,一些研究者还开发了多种灌注技术的联合应用,包括NRP与机器灌注(MP)以及双低温氧合机灌注(D-HOPE)的联合使用,均展现出良好的移植效果,为肝移植供体保存提供更多可能性.虽然许多学者认为NRP是一种获取更多高质量器官的保存方法,但有研究者质疑该技术的伦理问题.他们认为该技术违背死亡捐赠规则,NRP灌注程序中所涉及的操作可能导致患者的死亡,因此,确保患者的循环以及呼吸的永久性不可恢复状态以及在NRP期间确保脑部循环的缺失尤其重要.鉴于NRP在移植领域的重要性,笔者对NRP技术在cDCD中的应用进行归纳总结.

In recent years, the prevalence of metabolic-associated fatty liver disease (MAFLD) has reached pandemic proportions as a leading cause of liver fibrosis worldwide. However, the stage of liver fibrosis is associated with an increased risk of severe liver-related and cardiovascular events and is the strongest predictor of mortality in MAFLD patients. More and more people believe that MAFLD is a multifactorial disease with multiple pathways are involved in promoting the progression of liver fibrosis. Numerous drug targets and drugs have been explored for various anti-fibrosis pathways. The treatment of single medicines is brutal to obtain satisfactory results, so the strategies of multi-drug combination therapies have attracted increasing attention. In this review, we discuss the mechanism of MAFLD-related liver fibrosis and its regression, summarize the current intervention and treatment methods for this disease, and focus on the analysis of drug combination strategies for MAFLD and its subsequent liver fibrosis in recent years to explore safer and more effective multi-drug combination therapy strategies.

As the primary type of liver cancer, hepatocellular carcinoma (HCC) causes a large number of deaths every year. Despite extensive research conducted on this disease, the prognosis of HCC remains unclear. Recently, research has largely focused on extracellular vesicles (EVs), and they have been found to participate in various ways in the development of various diseases, including HCC, such as by regulating cell signaling pathways. However, recent studies have reported the mechanisms underlying the regulation of Wnt signaling by EVs in HCC, primarily focusing on the regulation of the canonical pathways. This review summarizes the current literature on the regulation of Wnt signaling by EVs in HCC and their underlying mechanisms. In addition, we also present future research directions in this field. This will deepen the understanding of HCC and provide new ideas for its treatment.

Hepatocellular carcinoma (HCC) being a leading cause of cancer-related death, has high associated mortality and recurrence rates. It has been of great necessity and urgency to find effective HCC diagnosis and treatment measures. Studies have shown that microvascular invasion (MVI) is an independent risk factor for poor prognosis after hepatectomy. The abnormal expression of biomacromolecules such as circ-RNAs, lncRNAs, STIP1, and PD-L1 in HCC patients is strongly correlated with MVI. Deregulation of several markers mentioned in this review affects the proliferation, invasion, metastasis, EMT, and anti-apoptotic processes of HCC cells through multiple complex mechanisms. Therefore, these biomarkers may have an important clinical role and serve as promising interventional targets for HCC. In this review, we provide a comprehensive overview on the functions and regulatory mechanisms of MVI-related biomarkers in HCC.