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Original Article Open Access
ATOX1 Promotes Hepatocellular Carcinoma Carcinogenesis via Activation of the c-Myb/PI3K/AKT Signaling Pathway
Qin Ouyang, Siyu Jia, Qianyu Zhu, Yanmeng Li, Huaduan Zi, Sisi Chen, Pingping He, Hengcheng Tang, Yanling Li, Anjian Xu, Bei Zhang, Xiaomin Wang, Xiaojuan Ou, Donghu Zhou, Jian Huang
Published online July 7, 2025
Journal of Clinical and Translational Hepatology. doi:10.14218/JCTH.2024.00422
Abstract
Despite advancements in diagnostic and therapeutic strategies, hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality. Antioxidant-1 (ATOX1) has been [...] Read more.

Despite advancements in diagnostic and therapeutic strategies, hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality. Antioxidant-1 (ATOX1) has been implicated in oncogenic processes across various cancer types; however, its specific role in HCC remains unclear. This study aimed to investigate the function of ATOX1 and its underlying molecular mechanisms in HCC.

Immunohistochemical analysis was conducted to assess ATOX1 expression in HCC tissues. Cell Counting Kit-8, colony formation, Transwell migration, flow cytometry, and reactive oxygen species (ROS) assays were employed to evaluate the malignant behaviors of tumor cells. A xenograft mouse model was employed to assess the effects of ATOX1 knockdown on tumor growth in vivo. DCAC50 treatment was performed to inhibit the copper transport function of ATOX1. RNA sequencing was conducted to explore the potential molecular mechanisms of ATOX1 in HCC.

ATOX1 expression was significantly elevated in HCC tumor tissues. ATOX1 promoted cell proliferation, colony formation, and migration. Knockdown of ATOX1 suppressed tumor growth in vivo. Mechanistically, ATOX1 activated c-Myb, and thus enhanced the malignant phenotype of HCC cells via activation of the PI3K/AKT signaling pathway. Additionally, ATOX1 reduced intracellular copper accumulation and inhibited ROS production and apoptosis. Inhibition of ATOX1 by DCAC50 decreased cell proliferation while increasing ROS levels and apoptosis in HCC cells. Notably, acetylcysteine reversed the reduction in c-Myb expression induced by ATOX1 knockdown.

ATOX1 may promote HCC carcinogenesis through the activation of the c-Myb/PI3K/AKT pathway and the inhibition of copper accumulation and oxidative stress.

Full article
Research Letter Open Access
Development and Validation of a Novel Noninvasive Model to Predict Liver Fibrosis Staging in Untreated Patients with Chronic Hepatitis B
Jianhua Hu, Xiaoli Zhang, Zhibo Zhou, Fangfang Geng, Hongyu Jia, Linfeng Jin, Weixiang Zhong, Guodong Yu, Xue Wen, Hainv Gao, Yida Yang
Published online July 7, 2025
Journal of Clinical and Translational Hepatology. doi:10.14218/JCTH.2025.00175
Review Article Open Access
Folate-biopterin Crosstalk in Human Disease
Mark D. Lucock, Robert J. Leeming
Published online July 4, 2025
Exploratory Research and Hypothesis in Medicine. doi:10.14218/ERHM.2025.00020
Abstract
The importance of putative folate-biopterin metabolic interactions lies in the role they may play in the expression of several clinically relevant phenotypes. However, to date, [...] Read more.

The importance of putative folate-biopterin metabolic interactions lies in the role they may play in the expression of several clinically relevant phenotypes. However, to date, clinical studies on folate-biopterin interactions have been limited. The purpose of this article was to highlight the close relationship between these two cofactors, which share structural similarities and exhibit overlapping metabolic pathways. This folate-biopterin crosstalk has generated several ideas and hypotheses that are critical to advancing the biochemical understanding of several important and seemingly disparate clinical and/or biologically important phenotypes. These phenotypes include melanization/pigmentation, phenylketonuria, autism, neural tube defects, affective disorders, and vascular disease. This review provides a timely, integrated overview of this important area of biochemistry, which is under-represented in the literature and would benefit from further scientific and clinical investigation using improved metabolite-specific analytical methodologies applied to clinically relevant questions.

Full article
Original Article Open Access
Cumulative Hepatitis B Surface Antigen/Hepatitis B Virus DNA Ratio in Immune-tolerant Hepatitis B Patients: A 10-year Follow-up Study
Dawu Zeng, Yanfang Huang, Sheng Lin, Naling Kang, Yanxue Lin, Jiaji Jiang, Yueyong Zhu, Qi Zheng, Jiming Zhang
Published online July 4, 2025
Journal of Clinical and Translational Hepatology. doi:10.14218/JCTH.2025.00205
Abstract
Patients with chronic hepatitis B virus (HBV) infection in the immune-tolerant phase may still experience hepatic inflammation and disease progression, and could benefit from early [...] Read more.

Patients with chronic hepatitis B virus (HBV) infection in the immune-tolerant phase may still experience hepatic inflammation and disease progression, and could benefit from early antiviral treatment. This study aimed to investigate changes in the cumulative hepatitis B surface antigen (HBsAg)/HBV DNA ratio in immune-tolerant patients during the transition to the immune-active phase, and to evaluate its potential in predicting the risk of disease progression.

This longitudinal study included 127 untreated immune-tolerant patients, who were followed for up to 10 years. An independent cohort of 109 subjects was retrospectively enrolled for external validation. The relationship between the cumulative HBsAg/HBV DNA ratio and the duration of immune tolerance or transition to the immune-active phase was examined. The predictive value of the ratio was assessed and validated.

The relationship between the cumulative HBsAg/HBV DNA ratio and disease progression risk showed a non-linear pattern: below a ratio of 1.791, the risk of disease progression decreased rapidly as the ratio increased; above 1.791, the risk plateaued. The area under the curve for predicting disease progression was 0.67, 0.64, and 0.85 for cumulative HBsAg, HBV DNA, and the HBsAg/HBV DNA ratio, respectively. Multivariable Cox regression analysis revealed the cumulative HBsAg/HBV DNA ratio as an independent predictor of disease progression, with higher ratios associated with a lower risk. Prediction models incorporating this ratio were developed and externally validated, demonstrating strong performance and clinical utility.

The cumulative HBsAg/HBV DNA ratio is an independent factor influencing the duration of immune tolerance and shows superior predictive performance. It may serve as a valuable marker for assessing the risk of disease progression in patients with chronic HBV infection.

Full article
Original Article Open Access
Clinical, Microbiological, and Antibiotic Treatment Characteristics of Bacterial Infections in Patients with Liver Cirrhosis in China: A Multicenter Study
Xiuding Zhang, Haoda Weng, Qinzhi Deng, Min Deng, Xuwei Wu, Zuxiong Huang, Shourong Liu, Rui Wu, Chunlian Ma, Yao Xu, Jianfeng Zhong, Jie Yang, Yinxia Wu, Huajiang Shen, Feng Ding, Fang Wang, Xuezhen Zhai, Chunxian Peng, Haotang Ren, Jie Jin, Xiangfei Xu, Xiaofei Li, Xiaoting Ye, Guoqing Qian, Shuilin Sun, Xuebing Yao, Haifeng Miao, Qianggu Xiao, Shaoheng Ye, Qing Zhang, Xinyi Xu, Xia Yu, Yue Yu, Yan Lan, Huilan Tu, Xianbin Xu, Xinrong Zhang, Rui Huang, Xiaohan Qian, Qiao Yang, Jifang Sheng, Yu Shi
Published online July 3, 2025
Journal of Clinical and Translational Hepatology. doi:10.14218/JCTH.2025.00211
Abstract
Epidemiological data on bacterial infections in cirrhosis in China remain limited. Therefore, we aimed to conduct a multicenter study to investigate the characteristics and outcomes [...] Read more.

Epidemiological data on bacterial infections in cirrhosis in China remain limited. Therefore, we aimed to conduct a multicenter study to investigate the characteristics and outcomes of patients with cirrhosis and bacterial infections in China.

We retrospectively enrolled 1,438 hospitalized adult patients with cirrhosis and bacterial or fungal infections from 24 hospitals across China between January 2018 and September 2024. Data on demographics, clinical features, microbiology, treatment, and outcomes were collected.

A total of 1,783 infection episodes were recorded, including 1,668 first infections and 115 second infections. Most infections were community-acquired (86.6%). Pneumonia was the most common infection type (26.7%), followed by spontaneous bacterial peritonitis (19.5%) and spontaneous bacteremia (14.1%). Among 754 pathogens isolated from 620 patients, Klebsiella pneumoniae (20.1%) was nearly as common as Escherichia coli (21.7%). Multidrug-resistant (MDR) organisms accounted for 41.0% of all isolates, with extended-spectrum β-lactamase-producing Escherichia coli being the most prevalent MDR strain (8.9% of patients). Adherence to empirical antibiotic treatment guidelines from the European Association for the Study of the Liver was significantly lower in this cohort compared to the global study (21.5% vs. 61.2%, P < 0.001), accompanied by a lower clinical resolution rate (63.5% vs. 79.8%, P < 0.001).

The clinical and microbiological characteristics of bacterial infections in patients with cirrhosis in China differ substantially from those reported in other regions. These findings highlight the need for region-specific management and prevention strategies, particularly in light of the changing microbiological landscape, high MDR prevalence, and suboptimal antibiotic practices.

Full article
Review Article Open Access
Polygenic Architecture of Dental Caries: Single Nucleotide Polymorphisms in Genetic Epidemiology
Luiz Alexandre Chisini, Luana Carla Salvi, Rodrigo Varella de Carvalho, Francine dos Santos Costa, Flávio Fernando Demarco, Marcos Britto Correa
Published online July 1, 2025
Gene Expression. doi:10.14218/GE.2025.00018
Abstract
This review presents the latest evidence on the link between genetic single nucleotide polymorphisms and dental caries, highlighting key genes and pathways involved, introducing [...] Read more.

This review presents the latest evidence on the link between genetic single nucleotide polymorphisms and dental caries, highlighting key genes and pathways involved, introducing foundational concepts, and discussing essential methodological considerations for future research. Several genes have been identified as significantly associated with caries experience, including those related to tooth mineral tissues, taste perception, salivary composition and flow, and immune response. Epistatic interactions appear to be crucial in explaining genetic influence. Inconsistencies in the literature are attributed to variations in caries classification, age groups, ethnic backgrounds, limited statistical power, and linkage disequilibrium. Population stratification often confounds results, and few studies adequately control for genetic ancestry. Ensuring Hardy-Weinberg equilibrium and accounting for linkage disequilibrium are essential to avoid bias. Bonferroni corrections for multiple comparisons are fundamental but rarely applied, contributing to inconsistent findings. In conclusion, genetic epidemiology studies suggest that dental caries has a genetic component, accounting for significant individual differences in disease risk.

Full article
Review Article Open Access
The Link Between Immune Aging and Type 2 Diabetes: A Review of Mechanisms and Implications
Swarup K. Chakrabarti, Dhrubajyoti Chattopadhyay
Published online July 1, 2025
Exploratory Research and Hypothesis in Medicine. doi:10.14218/ERHM.2025.00018
Abstract
Type 2 diabetes (T2D) is a metabolic disorder characterized by insulin resistance (IR), inflammation, and dysregulation in glucose metabolism. The disease is spreading globally, [...] Read more.

Type 2 diabetes (T2D) is a metabolic disorder characterized by insulin resistance (IR), inflammation, and dysregulation in glucose metabolism. The disease is spreading globally, partly due to aging, which can damage the immune system and speed up the progression of the metabolic disorder. This review primarily delves into the triggers for T2D within the framework of the ominous octet, which emphasizes 8 principal factors under the “ominous octet” framework that contribute to high blood glucose and associated metabolic disorders. The article studies the interplay of hyperinsulinemia, mitochondrial dysfunction (MD), and endoplasmic reticulum (ER) stress with immune aging in driving disease progression affecting each component of the octet. MD and ER stress can result in defects in insulin signaling, ultimately leading to β-cell death. Chronic inflammation associated with aging, also known as inflammaging, especially affects older adults by worsening IR and glucose regulation, which creates a continuous sequence of metabolic problems. Thus, the “ominous octet” framework provides fundamental knowledge to develop personalized treatment approaches that target metabolic dysfunction together with ER stress, MD, and immune system imbalances. These strategies show promising potential to improve treatments for T2D and may lead to better health outcomes for older adults dealing with this condition.

Full article
Original Article Open Access
Integrated Analysis of Serum and Fecal Metabolites Reveals the Role of Bile Acid Metabolism in Drug-induced Liver Injury: Implications for Diagnostic and Prognostic Biomarkers
Simiao Yu, Sici Wang, Ping Li, Haocheng Zheng, Jing Jing, Tingting He, Xia Ding, Ruilin Wang
Published online June 30, 2025
Journal of Clinical and Translational Hepatology. doi:10.14218/JCTH.2025.00073
Abstract
Drug-induced liver injury (DILI) represents a prevalent adverse event associated with medication use. However, the exact mechanisms underlying DILI remain incompletely understood, [...] Read more.

Drug-induced liver injury (DILI) represents a prevalent adverse event associated with medication use. However, the exact mechanisms underlying DILI remain incompletely understood, and the lack of specific diagnostic and prognostic biomarkers poses significant challenges to the clinical diagnosis and treatment of this condition. Consequently, our study aimed to endeavor to identify serum and fecal metabolic biomarkers, enabling more accurate DILI diagnosis and improved prediction of chronic progression.

Untargeted metabolomics analysis was performed on serum and fecal samples obtained from a cohort of 32 DILI patients (causality confirmed via the updated Roussel Uclaf Causality Assessment Method) and 36 healthy controls. Utilizing techniques such as partial least squares-discriminant analysis modeling and t-tests, we identified significantly differentially expressed metabolites and metabolite sets. Causality assessment was performed using the updated Roussel Uclaf Causality Assessment Method.

The findings from the analysis of serum and fecal metabolomics association pathways suggested that perturbations in bile acid metabolism might serve as potential mechanisms underlying the progression of DILI. Our study revealed 22 overlapping differential metabolites between serum and feces, displaying significant concentration differences between the DILI and healthy control groups. Notably, we identified chenodeoxycholic acid and deoxycholic acid as promising markers that not only distinguished DILI patients from healthy individuals but also exhibited predictive potential for DILI chronicity.

The integrated analysis of serum and fecal metabolites uncovers the significant disruption of bile acid metabolites as a key contributing factor in the pathogenesis of DILI. Our study offers promising potential biomarkers for the diagnosis and prognosis of DILI, paving the way for a novel perspective in the realm of DILI diagnosis and treatment.

Full article
Case Report Open Access
Pediatric Atypical Teratoid/Rhabdoid Tumor of the Cerebellum: A Case Report and Literature Review
Xing Huang, Yike Cai, Hong Lin
Published online June 30, 2025
Neurosurgical Subspecialties. doi:10.14218/NSSS.2025.00002
Abstract
Atypical teratoid/rhabdoid tumor (AT/RT) is a rare and highly aggressive embryonal tumor that predominantly affects infants and young children. This malignancy arises from primitive [...] Read more.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare and highly aggressive embryonal tumor that predominantly affects infants and young children. This malignancy arises from primitive neuroectodermal cells and exhibits heterogeneous differentiation into various embryonic tissues. Due to its rarity and complexity, diagnosing and managing AT/RT present significant challenges. Recent studies have summarized the key features of cerebellar and supratentorial AT/RT cases; however, critical gaps remain in understanding their diffuse leptomeningeal variants and long-term functional outcomes. Here, we report a case of a two-year-old child diagnosed with cerebellar AT/RT, who presented with vomiting and gait instability. The patient underwent a gross total resection followed by adjuvant radiotherapy and chemotherapy. Despite achieving radiological remission, the patient survived for only eight months and experienced severe neurological deficits, including persistent ataxia and recurrent infections. This case highlights the disconnect between surgical success and long-term quality of life. It underscores the importance of integrating molecular diagnostics and palliative care to address the multifaceted burden of AT/RT.

Full article
Review Article Open Access
miRNA Dysregulation of AGE/RAGE Pathway in Metabolic Syndrome: A Novel Analysis Strategy Utilizing miRNA-profiling Data
Bograya Maria, Voronova Sophia, Lopatin Mikhail, Vulf Maria, Natalia Todosenko, Litvinova Larisa
Published online June 30, 2025
Gene Expression. doi:10.14218/GE.2025.00039
Abstract
Metabolic syndrome (MetS) is associated with a plethora of different comorbidities. Exploring its key molecular mechanisms, such as advanced glycation end product and its receptor [...] Read more.

Metabolic syndrome (MetS) is associated with a plethora of different comorbidities. Exploring its key molecular mechanisms, such as advanced glycation end product and its receptor (AGE/RAGE) pathway, holds great potential. Numerous sources agree that targeting the AGE/RAGE pathway is a potential therapeutic strategy for MetS. However, the regulation of AGE/RAGE by microRNAs (miRNAs) in the context of MetS is still poorly understood. This review aimed to provide a systematic picture of the influence of miRNAs on AGE/RAGE in the context of MetS, with a particular focus on its ligands and receptors. This review achieves this in two ways: through an inductive “bottom-up” approach realized by a classical descriptive literature search, and through a deductive/synthetic “top-down” approach based on carefully selected miRNA profiling studies in MetS and its comorbidities. Although the initial inductive approach allowed the identification of some miRNAs of interest, almost all articles on this topic focus on the regulation of processes exclusively involved in atherogenesis. The new deductive approach has broadened the research horizon: It has enabled the discovery of new promising miRNAs and allowed for ranking different comorbid pathologies in MetS according to the degree of miRNA dysregulation of AGE/RAGE. Thus, in addition to atherosclerosis, significant miRNA dysregulation of AGE/RAGE was also described in MetS, particularly in immune cells, as well as in subcutaneous adipose tissue in obesity. This review, along with the novel approaches to systematizing the data contained therein may contribute to the understanding of MetS pathogenesis and the search for targets for the treatment of MetS.

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