Double-stranded linear DNA (dslDNA), considered to serve as a major precursor to integrated HBV DNA (iDNA), is generally located in the livers of patients with chronic HBV infection. Prior research has primarily focused on the role and mechanisms of HBV integration in the progression of hepatocellular carcinoma (HCC), demonstrating that iDNA can lead to genomic instability in the host and induce aberrant expression of host tumor-related genes around the integration sites, while viral proteins expressed by iDNA exhibit tumor-promoting effects. In recent years, the impact of iDNA-derived hepatitis B surface antigen on antiviral therapy in patients with chronic hepatitis B has received increasing attention with a deeper understanding of integrated HBV DNA. Consequently, the field has become a research hotspot and challenge in determining how to eliminate or silence iDNA to improve functional cure in patients with chronic hepatitis B. This paper aims to provide new sights to the clinical significance of iDNA and a theoretical basis for optimizing antiviral therapy strategies by summarizing the occurrence mechanisms of iDNA and its impact on the onset and progression of hepatocellular carcinoma and antiviral therapy for patients with chronic hepatitis B.

Human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV + OPSCC) generally has favorable outcomes yet remains prone to late recurrence. Durable control likely depends on persistent tumor-specific CD8+ T cells, but their persistence and function in metastasis are poorly understood.

We integrated bulk RNA sequencing (n = 56) with single-cell RNA and paired T-cell receptor (TCR) sequencing of tumor-infiltrating CD8+ T cells (n = 4), including a longitudinal primary-lung metastasis pair obtained three years after curative therapy. HPV genotyping, HLA typing, epitope prediction, and NFAT-reporter Jurkat-luciferase assays were used to identify and functionally validate HPV16 E6/E7-specific TCRs. Repertoire tracking and single-cell/bulk transcriptomics were evaluated.

HPV + tumors showed higher inferred CD8+ T cell infiltration and more favorable prognosis than HPV- tumors. Single-cell analysis revealed oligoclonally expanded exhausted clusters enriched in HPV tumor-specific CD8+ T cells. We isolated and functionally validated nine patient-derived HPV16 E6/E7-specific TCRs. High-avidity receptors recognizing an alternatively spliced region in E6 (aa 49-110; E6*) persisted in metastatic lesions, whereas lower-avidity clones, including an E7_11-19-specific TCR currently under clinical investigation, were lost. Compared with the primary tumor, metastatic lesions showed reduced stem-like/TCF7-associated CD8+ T-cell populations and enrichment of HPV-specific CD8+ T cells expressing KLRB1 and ZNF683, consistent with a tissue-adapted TRM-like transcriptional state with inhibitory signaling features.

High-avidity, KLRB1 + HPV-specific CD8+ T cells represent a persistent effector subset with prognostic and therapeutic relevance to HPV + OPSCC. Their persistence in metastatic lesions and association with reduced recurrence risk support further investigation of KLRB1-associated HPV-reactive T-cell states as biomarkers and immunotherapeutic targets.

Bladder cancer (BC) is considered one of the most prevalent malignant cancers of the urinary system. Recently, autophagy was found to be involved in tumor development.

Investigating the link between BC and autophagy, highlighting the role of ER stress in tumor growth and invasiveness.

Sixty urothelial carcinoma patients recruited to this study were divided into 2 groups: Low-grade BC (LGBC) and High-grade BC (HGBC), which were further classified as muscle-invasive (HGMI) or non-muscle-invasive (HGNMI). Control tissue samples were collected from the safety margin. Levels of ATG5 and caspase 3 were determined using qRT-PCR; CHOP levels by ELISA; and malondialdehyde using the lipid peroxide assay kit. LC3A expression was detected by immunohistochemistry.

Significant upregulation of tissue levels of ATG5, CHOP, MDA and LC3A was observed in tumor tissue samples from all groups compared to control, and in MIBC compared to NMIBC, with significant relations between their levels and LN involvement. Caspase-3 was significantly downregulated in HGBC compared to LGBC. Levels of ATG5, CHOP and LC3A can discriminate between normal and malignant urothelial tissue and between invasive and non-invasive bladder cancer.

Expression of tissue autophagy biomarkers is associated with aggressive clinicopathological features (muscle invasion) in bladder cancer.

Prostate cancer (PCa) is among the highest incidence malignancies in men, with high rates of inevitable resistance development, relapse, and mortality. Castration-resistant prostate cancer (CRPC) continued to pose substantial therapeutic challenges, highlighting the urgent need for effective treatment options. This study assessed the marine cembranoid sarcophine activity against the progression and recurrence of the metastatic CRPC (mCRPC) in mouse xenograft models. Protein and phosphorylation levels were assessed by immunoblotting and mRNA expression by qPCR and RNA sequencing. The in vivo efficacy was evaluated through tumor progression over 3 weeks followed by primary tumor excision and recurrence monitoring over an 8-week course. Sarcophine significantly reduced the mCRPC CWR-R1ca tumor volume by 74.1% and suppressed the epigenetic regulators EZH2 and SMYD2; lineage plasticity factors ASCL1 and BRN2; Wnt/stemness signaling markers β-catenin and LGR6; AKT total expression and activation; and invasion-associated proteins TRPC4 and MMP2 in primary tumors. Sarcophine effectively prevented the mCRPC locoregional recurrence, as well as lung and spleen distant recurrences, and effectively reduced recurrence in other organs. Transcriptomics-RNA-Seq analysis of primary tumors identified 2697 downregulated and 3534 upregulated genes, indicating broad transcriptional reprogramming following sarcophine treatments. These findings demonstrate coordinated suppression of multi-oncogenic pathways and validate the therapeutic potential of sarcophine to control mCRPC.

Hepatitis B virus (HBV) infection remains a major global health burden, with chronic infection leading to severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). HBV-encoded X protein (HBx) plays a critical role in viral replication and pathogenesis by modulating host cellular processes, including autophagy and lysosomal function. However, the molecular mechanisms by which HBx disrupts lysosomal biogenesis and autophagic degradation remain elusive. In this study, we show that HBx downregulates the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, which leading to impaired lysosomal acidification and autophagosome-lysosome fusion. Mechanistically, HBx-mediated TFEB downregulation involves the CUL4A (Cullin 4A)/CUL4B (Cullin 4B)-DDB1 (DNA damage-binding protein 1) E3 ubiquitin ligase complex and is dependent on the DDB1-interacting motif in HBx. HBx mutants defective in DDB1 binding (HBx^R96E and HBx^ΔDBD) fail to downregulate TFEB or impair lysosomal function. Collectively, our findings identify a pathway by which HBx disrupts lysosomal function via CUL4A/CUL4B-DDB1-dependent TFEB downregulation, providing insights into HBV-associated liver pathogenesis and highlighting potential targets for therapeutic intervention.

Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by rapid progression, therapeutic resistance, and poor patient prognosis. Emerging evidence highlights the critical role of long non-coding RNAs (lncRNAs) in GBM pathogenesis, particularly through their interactions with RNA-binding proteins (RBPs). These interactions form complex regulatory networks that influence multiple GBM hallmarks, such as sustained proliferation, induction of angiogenesis, and immune evasion. Additionally, these interactions play a pivotal role in maintaining glioma stem-like cells, a subpopulation responsible for tumor recurrence and resistance to conventional therapies. Understanding the mechanistic basis of lncRNA-RBP interactions offers promising opportunities for therapeutic intervention. Targeting these networks could enable the development of novel and more effective treatment strategies. This review provides an in-depth analysis of the molecular mechanisms by which lncRNA-RBP complexes promote GBM development.

Sarcomas with Murine Double Minute 2 (MDM2) amplification are considered potential candidates for MDM2-targeted therapy. However, the limited efficacy of MDM2 inhibitor monotherapy suggests that additional biological factors may influence tumor behavior and prognosis. This study investigated the relationship between MDM2 expression and the Complexity Index in SARComas (CINSARC) transcriptomic signature, a gene expression signature that reflects cell division and chromosomal instability in soft tissue sarcomas. In the public GSE21050 dataset comprising 310 soft tissue sarcomas, the MDM2-low/CINSARC-low subgroup showed the most favorable metastasis-free survival, whereas the MDM2-high/CINSARC-low subgroup had an unfavorable metastasis-free survival comparable to that of the MDM2-high/CINSARC-high group. Among the representative genes in the 12q13-15 region, fibroblast growth factor receptor substrate 2 (FRS2) showed a strong positive correlation with MDM2 expression, but no significant correlation with CINSARC, suggesting an association independent of proliferative capacity. These findings suggest that proliferation-based risk assessment alone may underestimate the metastatic risk of a subset of MDM2-high sarcomas, and FRS2 may present a biologically relevant marker of aggressive behavior independent of tumor proliferation.

The pathogenesis of Hepatitis B virus (HBV)-related cirrhosis and hepatocellular carcinoma (HCC) has not been fully elucidated at present. While METTL14 is crucial in innate immunity, its specific role in HBV-related liver disease progression is unclear. We analyzed METTL14 expression in patient tissues and bioinformatics datasets. Mouse models of HBV-related cirrhosis and HCC were established to evaluate liver injury, fibrosis, and tumorigenesis. Mechanistic studies utilized MeRIPqPCR, RIP, and Actinomycin D assays, and hepatocyte-stellate cell co-cultures to investigate METTL14's impact on cGAS mRNA stability, the cGAS-STING pathway, and IFNB1 secretion. METTL14 was downregulated in HBV infection, cirrhosis, and HCC. METTL14 knockdown aggravated liver injury, fibrosis, and tumor formation in mice. Mechanistic studies revealed that METTL14 overexpression in HBV-infected hepatocytes promoted the degradation of cGAS mRNA by increasing its m6A modification, thereby suppressing the cGAS-STING pathway activation and IFNB1 release. Consequently, METTL14 overexpression inhibited stellate cell activation, which was reversed by cGAS-STING agonists. Downregulation of METTL14 reduces the degradation of cGAS mRNA through m⁶A modification, facilitates the cGAS-STING pathway activation and IFNB1 release, thereby accelerating HBV-related cirrhosis and HCC progressions.

Background/Objectives: Periductal fibrosis (PDF) is a common hepatobiliary abnormality associated with chronic Opisthorchis viverrini infection and may represent an ultrasonographic marker of chronic biliary injury in liver fluke-endemic regions. This systematic review and meta-analysis evaluated the association between ultrasound-defined PDF and cholangiocarcinoma (CCA)-related outcomes and summarized the prevalence of overall PDF and advanced periductal fibrosis (APF) in endemic populations. Methods: PubMed, Embase, and Scopus were searched from database inception to April 2026, supplemented by manual screening of reference lists. Observational studies reporting PDF prevalence and/or the association between PDF and CCA-related outcomes were included. Pooled odds ratios (ORs) and prevalence estimates were calculated using random-effects models. Five studies met the inclusion criteria. Results: Three studies involving 758,686 participants were included in the pooled association analysis. Ultrasound-defined PDF was associated with higher odds of CCA-related outcomes, including confirmed CCA, incident CCA, and clinically suspected CCA, with a pooled OR of 2.77 (95% CI: 2.24-3.44; I² = 0%). Because outcome definitions, effect measures, adjustment status, and PDF exposure categories varied across studies, this estimate should be interpreted as a summary association rather than as a precise estimate of confirmed CCA risk. Four studies involving 759,117 participants contributed to the overall PDF prevalence analysis, whereas three studies reported APF prevalence data. Prevalence estimates varied substantially across endemic settings, with extreme between-study heterogeneity. Conclusions: Overall, ultrasound-defined PDF may help identify individuals who warrant closer surveillance or further evaluation; however, it should not be interpreted as a definitive histopathological diagnosis or a proven causal precursor of CCA. Further prospective studies using standardized fibrosis definitions, blinded ultrasonographic assessment, confirmed or incident CCA outcomes, and adjustment for O. viverrini infection-related factors and other key confounders are needed to validate the role of PDF in CCA risk stratification.

Objective: To analyze the epidemiological characteristics of incidence and mortality of esophageal cancer in Shandong Province from 2012 to 2023. Methods: Data on incidence and mortality of esophageal cancer from 2012 to 2023 were obtained from the Shandong Provincial Cancer Registry. Crude and age-standardized rates stratified by year, gender and urban-rural residence were calculated using the standardized population of China in 2000. Joinpoint Regression Program 4.8.0.1 was adopted to estimate the annual percent change (APC) and average annual percent change (AAPC). Results: Both crude and age-standardized incidence rates of esophageal cancer in Shandong Province declined remarkably from 2012 to 2023, with the AAPC of -4.59% (P<0.001) and of -7.67% (P<0.001), respectively. Males had higher crude and age-standardized incidence rates than females, and rural areas presented higher rates than urban areas. For males, the AAPCs of crude and age-standardized incidence rates were of -3.33% (P<0.001) and of -6.89% (P<0.001). For females, the values were of -6.29% (P<0.001) and of -10.73% (P<0.001). In urban areas, the AAPCs were of -4.59% (P=0.001) and of -6.68% (P<0.001), while those in rural areas were of -4.57% (P<0.001) and -8.16% (P<0.001). Crude and age-standardized mortality rates also showed a significant downward trend, with the AAPC of of -4.48% (P<0.001) and of -8.26% (P<0.001). Mortality rates were higher in males and rural populations. The AAPCs of crude and age-standardized mortality rates were of -3.70% (P<0.001) and of -5.53% (P=0.003) in males, and of -7.92% (P=0.001) and of -11.41% (P<0.001) in females. In rural areas, the corresponding AAPCs were of -4.64% (P<0.001) and of -8.49% (P<0.001). No obvious trend was observed in the urban crude mortality rate. The age-standardized mortality rate had no significant change from 2012 to 2014, and decreased significantly from 2014 to 2023 (APC= -7.68%, P<0.001). Age-specific incidence and mortality rose rapidly after 45 years and peaked in the 80-84 age group. Conclusion: The incidence and mortality of esophageal cancer have decreased significantly in Shandong Province in the past decade, with obvious gender and urban-rural disparities.