Clinical Epigenetics最新文献

{"title":"Epigenetic editing and epi-drugs: a combination strategy to simultaneously target KDM4 as a novel anticancer approach.","authors":"Federica Sarno, Jim J Jacob, Roos E Eilers, Angela Nebbioso, Lucia Altucci, Marianne G Rots","doi":"10.1186/s13148-025-01913-0","DOIUrl":"https://doi.org/10.1186/s13148-025-01913-0","url":null,"abstract":"<p><p>KDM4-A/B/C, preferentially demethylating di- and tri-methylated lysine 9 on histone H3, are overexpressed in cancers and considered interesting therapeutic targets. Consequently, KDM4 inhibitors have been developed to block their enzymatic activity. However, the potential lack of specificity of such small molecules (epi-drugs) may contribute to dose-limiting toxicities. In the pursuit of more specific interventions, epigenetic editing (epi-editing) has emerged as a powerful tool to modulate gene expression by modifying the epigenetic profile of specific genomic locations. The recently developed CRISPRoff (dCas9 fused to DNMT3A/3L and KRAB), guided by sgRNAs, is successfully used for gene repression by introducing methylation of DNA and (indirectly) of histones at the targeted genomic region. We propose that combining epi-editing (here to prevent the expression of KDM4) with epi-drugs (to inhibit the KDM4 protein activity) may represent a novel path for synergistic anticancer effects through simultaneous inhibition of gene expression and protein activity. Upon validating the downregulation of KDM4A in HEK293T cells through epi-editing, we demonstrated its repression in colon, breast and hepatocellular carcinomas which was effective in preventing (breast, MCF7) or inhibiting (colon, HCT116) cancer cell growth. Anticancer effect was also confirmed for these cell lines using the KDM4 inhibitor QC6352. In parallel, our studies demonstrate a previously unnoticed increase in the expression of KDM4-A/B/C genes following the inhibition of protein activity using the pan-KDM4 inhibitors QC6352 and JIB-04. Importantly, this induction of gene expression was fully prevented or even further inhibited by epi-editing. Then, we assessed the efficacy of our dual-targeted silencing approach in cancer cells and demonstrated that the inhibition in cancer cell growth by epi-drug or epigenetic editing could be further improved by combining the treatments. Building upon these findings, we introduce a novel, potentially synergistic, therapeutic strategy that combines epi-drug administration with epi-editing. This innovative approach aims to reduce drug toxicity and the potential development of resistance by preventing drug-induced upregulation of target enzyme expression, thereby further increasing anticancer effects.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"105"},"PeriodicalIF":4.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"cfDNA methylation detection as potential liquid biopsy of multiple organ injury in myocarditis patients.","authors":"Yangchao Zhao, Yujia Wang, Xi Zhao, Xin Zhang, Haoyan Wang, Liang Cui, Huifen Wang, Weiwei Zhu, Boyan Li, Yanjun Zhou, Jun Li, Guowei Fu, Yiheng Zhou, Pengwei Sun, Jing Bai, Xuefeng Xia, Xin Yi, Ling Yang, Chaoqun Chen, Junnan Tang, Ang Li, Zujiang Yu","doi":"10.1186/s13148-025-01914-z","DOIUrl":"https://doi.org/10.1186/s13148-025-01914-z","url":null,"abstract":"<p><p>Myocarditis is inflammatory injury of the myocardium and causes approximately 30,000 deaths globally each year. Fulminant myocarditis is an extremely severe form of myocarditis. Currently, the clinical evaluation of myocarditis and fulminant myocarditis is primarily based on symptoms, ECG findings, and biochemical markers. Cardiac magnetic resonance and endomyocardial biopsy can provide further support for the diagnosis, but both have limitations in routine practice. Recent studies have shown that cell-free DNA (cfDNA) has distinct methylation patterns depending on the organ of origin, suggesting new possibilities for tracking specific types of organ damage. The core mechanism of fulminant myocarditis is a cytokine storm, leading to multiorgan damage, differing from clinically suspected myocarditis. We performed Genome-wide cfDNA methylation detection on plasma from 20 healthy donors and 22 patients (fulminant myocarditis: clinically suspected myocarditis = 9:13, COVID-19 positive: COVID-19 negative = 14:8) and found that cfDNA can be used to specifically identify early multiorgan damage caused by fulminant myocarditis, and its AUC is superior to traditional biochemical indicators such as troponin, high-sensitivity troponin, and lactate dehydrogenase. This is critically important for the timely clinical recognition and treatment of this condition. Furthermore, our study findings suggest that SARS-CoV-2 infection may exacerbate the severity of myocarditis and multiorgan damage. In summary, cfDNA shows great potential as a noninvasive, early, and sensitive biomarker for reflecting disease severity and systemic injury in fulminant myocarditis, which may help guide earlier risk stratification and intervention.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"106"},"PeriodicalIF":4.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes of methylation at enhancers appear to be essential for HIV infection progression.","authors":"Olga Taryma-Leśniak, Jan Bińkowski, Kaja Mielczak, Bogusz Aksak-Wąs, Malwina Karasińska-Cieślak, Marta Sobalska-Kwapis, Dominik Strapagiel, Miłosz Parczewski, Tomasz Kazimierz Wojdacz","doi":"10.1186/s13148-025-01910-3","DOIUrl":"https://doi.org/10.1186/s13148-025-01910-3","url":null,"abstract":"<p><strong>Background: </strong>We studied the influence of the European HIV-1 subtype B (most common in the Western and Central Europe) and subtype A6 (prevalent in Eastern Europe including Ukraine and Russia) on host methylome during infection progression and in virus-subtype-specific manner.</p><p><strong>Results: </strong>Our results show that regardless of virus subtype, in the initial phase of the infection, HIV-related methylation changes more frequently affect parts of the genome with low expression activity including heterochromatin and quiescent regions. But, at stage four of the infection regions of the genome harboring HIV-related methylation changes are enhancers. We further showed that the effect of each of the virus subtypes on host methylome is to a large extent similar. And both virus subtypes appear to induce hypomethylation of loci associated with key pathways involved in viral infection such as 'type I interferon signaling pathway,' 'innate immune response' or 'negative regulation of viral genome replication.' Nevertheless, our results also indicate that each of the virus subtypes at least to some extent affects host methylome in virus-subtype-specific manner. Lastly, we showed that infection progression-related methylation changes that we identified are reversed with antiretroviral therapy.</p><p><strong>Conclusions: </strong>We have shown that progression of HIV infection is associated with hypomethylation of enhancers regardless of virus subtype. This suggests that methylation changes at the enhancers may be key for infection progression. However, we also identified methylation changes indicating that, each of the virus subtypes affects host methylome in specific manner, but these findings need to be confirmed in studies that include larger number of participants.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"104"},"PeriodicalIF":4.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between pace of biological aging and cancer and the modulating role of physical activity: a national cross-sectional study.","authors":"Jingying Nong, Yu Wang, Yi Zhang","doi":"10.1186/s13148-025-01912-1","DOIUrl":"10.1186/s13148-025-01912-1","url":null,"abstract":"<p><strong>Background: </strong>Cancer remains a serious public health problem impeding gains in life expectancy. Epigenetic clocks, derived from sets of DNA methylation CpGs and mathematical algorithms, have demonstrated a remarkable ability to indicate biological aging and age-related health risks. Dunedin(P)ace(o)f(A)ging(m)ethylation is a single-timepoint DNA methylation clock. It is an aging speedometer rather than a state measure. The association between the DunedinPoAm-measured pace of biological aging and cancer risk based on a nationally non-institutionalized sample remains to be elucidated. Physical activity, a modifiable lifestyle factor, is associated with delayed biological aging and lower risks of developing cancer. We hypothesized that DunedinPoAm-measured pace of biological aging is positively associated with cancer risk, and physical activity moderates this association.</p><p><strong>Results: </strong>In total, 2,529 participants aged 50 or older from the National Health and Nutrition Examination Survey (NHANES) 1999-2002 were included. Weighted logistic regression calculating odds ratios (OR) and 95% confidence intervals (CI) showed that when scaled per 1-SD increase, DunedinPoAm was positively associated with cancer risk (OR, 95% CI) (1.21, 1.05-1.39) in the crude model and adjusted for age and sex (1.19, 1.01-1.40). Individuals of high DunedinPoAm tertile had a 68% (95% CI 1.16-2.43) increase in cancer risk compared with the low tertile (P trend < 0.001). As hypothesized, effect modification by physical activity was significant (P interaction = 0.013). The association was apparent in physically inactive participants (1.52, 1.16-2.00), whereas insignificant in physically active individuals (1.08, 0.89-1.32). Exploratory interaction analyses for other covariates showed significant effect modification by age (> 65 years, 1.38, 1.08-1.77 vs 50-65 years, 1.00, 0.79-1.27).</p><p><strong>Conclusion: </strong>The study supported the hypothesis by demonstrating a positive association between the DunedinPoAm-measured pace of biological aging and cancer risk and a modulating role of physical activity. Physically inactive individuals or participants over 65 years showed increased susceptibility to this association. These findings suggest that incorporating the DunedinPoAm-measured pace of biological aging into cancer screening strategies may benefit those with physically inactive lifestyles and older individuals. Whether physical activity can mitigate the increased risk of cancer in individuals with a faster pace of biological aging needs to be validated in further interventional cohort studies.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"103"},"PeriodicalIF":4.8,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic silencing and CRISPR-mediated reactivation of tight junction protein claudin10b (CLDN10B) in renal cancer.","authors":"Sarah Arroyo Villora, Yufen Zhao, Paula Castellanos Silva, Alba A Hahn, Vivien Olanin, David Groll, Sandra Maurer, Vera Roetzer, Witold Szymanski, Tara Procida-Kowalski, Niklas Philipp, Aline Koch, Marek Bartkuhn, Johannes Graumann, Richard Volckmann, Jan Koster, Oliver Rossbach, Denise Salzig, Reinhard Dammann, Cornelia Sigges, Jan Halbritter, Silke Haerteis, Antje Maria Richter","doi":"10.1186/s13148-025-01911-2","DOIUrl":"10.1186/s13148-025-01911-2","url":null,"abstract":"<p><strong>Background: </strong>The kidney's tubular system relies on cell polarity and tight junctions to maintain structure and function and disruptions contribute to diseases like cancer. Loss of tight junction proteins such as Claudins can actively contribute to tumorigenesis.</p><p><strong>Results: </strong>We aimed to identify biomarkers for renal carcinoma, after kidney transplantation and conventional kidney tumors. We identified the epigenetic silencing of the Claudin 10 gene isoform B (CLDN10B) through DNA hypermethylation in renal cancers, including clear cell (ccRCC), papillary (pRCC) and post-transplantation renal carcinoma (PT-ccRCC). In contrast, CLDN10A was hypomethylated in ccRCC and pRCC. Differential methylation of the isoforms discriminates RCC from other malignancies. The epigenetic alteration of CLDN10B significantly correlated with reduced patient survival and advanced tumor staging. CLDN10B overexpression or induction significantly inhibited migration, cell cycle progression, and cellular growth. Using a CRISPR-based epigenetic editing tool reactivated CLDN10B to its endogenous level using VP160 and TET1 by promoter demethylation and significantly demonstrated its tumor-suppressive effects in 2D and 3D cell models.</p><p><strong>Conclusion: </strong>Our findings suggest that CLDN10B acts as a tumor suppressor, and its epigenetic regulation may represent a therapeutic target for RCC. Ultimately, understanding CLDN10B's regulation and function could provide new insights into renal cancer treatment.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"102"},"PeriodicalIF":4.8,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multi-omics and mediation-based genetic screening approach identifies STX4 as a key link between epigenetic regulation, immune cells, and childhood asthma.","authors":"Yuan Zhang, Xiaochen Du, Yujuan Yang, Yaqiong Ren, Lijun Zhou, Jun Hua, Hongying Wang","doi":"10.1186/s13148-025-01908-x","DOIUrl":"10.1186/s13148-025-01908-x","url":null,"abstract":"<p><strong>Background: </strong>Childhood asthma presents a multifaceted immune-driven pathology shaped by genetic, epigenetic, and immune regulatory interactions. Despite extensive genome-wide analyses pinpointing multiple susceptibility loci, the precise functional contributors to asthma pathogenesis remain elusive. This study employs a comprehensive multi-omics framework and Mendelian randomization (MR) analysis to systematically identify and validate key genetic determinants implicated in childhood asthma.</p><p><strong>Methods: </strong>A genome-wide screening of over 19,000 human genes was performed to identify cis-eQTL-regulated genes associated with childhood asthma. Two-sample MR was conducted to assess causality, followed by Summary-based Mendelian Randomization (SMR) to validate findings in independent datasets. Colocalization analysis determined whether gene expression and asthma GWAS signals share a common causal variant. Protein quantitative trait loci (pQTL) analysis further validated gene associations at the protein level. DNA methylation quantitative trait loci (mQTL) MR and mediation analysis explored epigenetic regulatory mechanisms, while linkage disequilibrium score regression (LDSC) quantified genome-wide genetic correlations. Immune cell mediation analysis examined potential immune-driven effects, and Phenome-Wide Association Study (PheWAS) evaluated pleiotropy and therapeutic safety.</p><p><strong>Results: </strong>Following systematic screening, STX4 emerged as a strong candidate gene for childhood asthma. MR and SMR analyses confirmed its causal role, while colocalization analysis provided robust genetic evidence supporting STX4's regulatory influence on childhood asthma susceptibility. pQTL validation confirmed that STX4's effects extend to the protein level, strengthening its biological relevance. DNA methylation analysis revealed key CpG (Cytosine-phosphate-Guanine) sites regulating STX4 expression, with higher methylation levels reducing childhood asthma risk. Immune cell mediation analysis demonstrated that STX4 influences childhood asthma risk via CD4+ and CD8+ T cell subsets. LDSC analysis reinforced a significant genetic correlation between STX4 and childhood asthma, while PheWAS detected no major pleiotropy, suggesting that STX4 is a specific and promising therapeutic target.</p><p><strong>Conclusions: </strong>This study systematically identifies and validates STX4 as a key genetic regulator in childhood asthma by integrating large-scale genetic, epigenetic, and immune regulatory data. These findings provide strong evidence for STX4's role in childhood asthma pathogenesis, highlighting STX4 as a potential target for future precision therapies in childhood asthma.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"101"},"PeriodicalIF":4.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restoring endogenous Dlg4/PSD95 expression by an artificial transcription factor ameliorates cognitive and motor learning deficits in the R6/2 mouse model of Huntington's disease.","authors":"Germán Fernández, Kevin Leiva, Fernando J Bustos, Brigitte van Zundert","doi":"10.1186/s13148-025-01903-2","DOIUrl":"10.1186/s13148-025-01903-2","url":null,"abstract":"<p><strong>Background: </strong>Huntington's disease (HD) is an incurable hereditary disorder caused by an expansion of CAG repeats in exon 1 of the Huntingtin gene (HTT). HD is characterized by motor dysfunction and cognitive decline. The pathophysiology of HD begins in cortico-striatal circuits and later spreads to other brain regions, notably the hippocampus. At the cellular level, structural changes in synapses have been observed prior to neuronal degeneration, significantly disrupting the formation and maintenance of neuronal circuits. The postsynaptic density protein 95 (PSD-95, hereafter Dlg4/PSD95) is a key synaptic plasticity protein reduced in HD and other neurodegenerative diseases such as Alzheimer's disease (AD). Epigenetic silencing of plasticity and memory genes contributes to AD pathology and cognitive impairment. To restore endogenous Dlg4/PSD95 expression in AD, we previously developed an epigenetic editing strategy where a zinc finger DNA-binding domain targeting the Dlg4/PSD95 gene promoter was fused to the transactivation domain VP64 and driven under a CMV promoter. AAV-PhP.B-mediated delivery of this artificial transcription factor (ATF) CMV-PSD95-6ZF-VP64 improved cognition in an AD mouse model. Here, we assessed the therapeutic potential of AAV9-mediated delivery of the synapsin-driven ATF PSD95-6ZF-VP64 in the R6/2 HD mouse model.</p><p><strong>Results: </strong>Consistent with the previous studies, R6/2 mice exhibited reduced hippocampal Dlg4/PSD95 mRNA and protein levels in young adulthood (7 weeks), which persisted into early adulthood (14 weeks). Starting at adolescents (4 weeks), the R6/2 mice also displayed motor (i.e., accelerated rotarod) and cognitive (i.e., Barnes maze and object location memory) impairments. In wild-type primary hippocampal cultures, AAV9-PSD95-6ZF-VP64 led to an increase in synaptic PSD-95 clusters and spine size. Intracerebroventricular injections of neonatal R6/2 mice with AAV9-PSD95-6ZF-VP64 elevated hippocampal Dlg4/PSD95 expression levels to those observed in control non-transgenic mice. Importantly, AAV9-PSD95-6ZF-VP64 effectively improved hippocampal-dependent deficits in spatial learning and memory in young adult HD mice, as well as impairments in motor coordination and motor skill learning, with these benefits persisting into adulthood.</p><p><strong>Conclusion: </strong>This work validates Dlg4/PSD95 as a key player in the prodromal phase of HD pathology and establishes the ATF PSD95-6ZF-VP64 as an attractive therapeutic tool for treating the disease's early phase.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"100"},"PeriodicalIF":4.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multi-omics prognostic model of cuproptosis affects the prognosis of stomach adenocarcinoma.","authors":"Yinying Wu, Yangwei Fan, Xuyuan Dong, Danfeng Dong, Yu Shi, Meichen Wang, Jia Wang, Yuqian Yang, Nan Yang, Fengyun Ou, Enxiao Li","doi":"10.1186/s13148-025-01894-0","DOIUrl":"10.1186/s13148-025-01894-0","url":null,"abstract":"<p><strong>Background: </strong>Cuproptosis, a form of cell death associated with copper ions, has been linked to the pathogenesis of various cancers, including gastric cancer. Investigating the role of cuproptosis-related genes through multi-omics analysis can enhance our understanding of disease mechanisms and improve prognosis prediction.</p><p><strong>Objective: </strong>This study aims to elucidate the role of cuproptosis-related genes in gastric cancer from a multi-omics perspective.</p><p><strong>Materials and methods: </strong>We utilized multi-omics sequencing data from TCGA and GEO databases to explore the relationships between cuproptosis genes and gastric carcinogenesis, clinical phenotypes, and prognosis. This analysis encompassed mutation, copy number variation, methylation, mRNA expression, alternative splicing, and APA alterations. Additionally, we examined the regulatory roles of cuproptosis genes in gastric cancer through ceRNA interactions, gene mutations, and DNA methylation. A multi-omics prognostic model for gastric cancer was subsequently constructed.</p><p><strong>Results: </strong>Our findings revealed that CDKN2A was the most frequently mutated gene in gastric cancer. Overall mutations in cuproptosis genes and copy number alterations of PDHB significantly impacted gastric cancer prognosis. Methylation, alternative splicing, and APA alterations of CDKN2A also influenced patient outcomes. Notably, MTF1, a key gene in cuproptosis, was found to affect apoptosis and invasion in gastric cancer cell lines.</p><p><strong>Conclusion: </strong>We successfully developed a multi-omics prognostic model for gastric cancer that offers significant predictive value for patient outcomes.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"99"},"PeriodicalIF":4.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A liquid biopsy approach detects HCC and identifies GJA4 as a potential biomarker for HBV-HCC via plasma cfDNA methylome profiling.","authors":"Jialing Sun, Xinfeng Sun, Weihuang He, Bingding Huang, Wenxing Feng, Zhiyi Han, Ruyun Ruan, Yuanke Pan, Jinxin Zhu, Jing Li, Xin Zhong, Mengqing Ma, Rui Hu, Minling Lv, Qi Huang, Wei Zhang, Mingji Feng, Jinyu Yi, Pin Cui, Xiaozhou Zhou","doi":"10.1186/s13148-025-01909-w","DOIUrl":"10.1186/s13148-025-01909-w","url":null,"abstract":"<p><strong>Background: </strong>Early detection of hepatocellular carcinoma (HCC) can greatly improve the survival rate of patients. Plasma cfDNA methylation has been shown to have the potential to be a non-invasive method for diagnosing HCC. However, the identified HCC plasma cfDNA methylation sites were less sensitive to early HCC diagnosis. Therefore, we aimed to develop a highly sensitive marker panel based on cell-free DNA (cfDNA) methylation for the detection of HCC.</p><p><strong>Methods: </strong>The study included 374 participants, including 102 healthy individuals, 51 HBV patients, 50 cirrhosis patients, and 171 HCC patients (56 at stage 0 or A according to BCLC staging). Two cfDNA methylation sequencing assays (whole genome bisulfite sequencing (WGBS) and targeted bisulfite sequencing (TBS)) were used along with machine learning modeling to detect HBV-related HCC based on differentially methylated regions (DMR) among the four participant groups.</p><p><strong>Results: </strong>TBS analysis achieved an overall sensitivity of 96.67% at a specificity of 93.7% than alpha-fetoprotein (AFP) of 18%-60%, to discriminate all stages of HCC patients from healthy people, and sensitivity of 90.0% at a specificity of 93.75% to discriminate early-stage HCC patients from healthy people. A number of significant DMRs between HCC and non-cancer groups were identified, providing candidate biomarkers for HCC detection. Among these DMRs, one that locates in the promoter region of GJA4, was found to be consistently present in the whole process of HBV-related HCC carcinogenesis. Using data from TCGA, comparison of expression profile of GJA4 between 160 healthy people and 369 HCC patients further supported this scenario.</p><p><strong>Conclusions: </strong>This study provides biomarkers for detecting, staging and early detection of HCC using plasma cfDNA methylome profiling. Additionally, the dynamic alteration of GJA4 promoter methylation may serve as a molecular clue for studying HBV-related HCC carcinogenesis and prognosis.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"98"},"PeriodicalIF":4.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EZH1 deficiency promotes ferroptosis resistance by activating NRF2 in sepsis-associated liver injury.","authors":"Meihua Mei, Ying You, Ningxin Tan, Xiaoshun He, Junqi Huang","doi":"10.1186/s13148-025-01892-2","DOIUrl":"10.1186/s13148-025-01892-2","url":null,"abstract":"<p><p>Sepsis-associated acute liver injury (SALI) is a major clinical complication of sepsis due to excessive, unfettered inflammation. In recent years, the role of epigenetic regulatory mechanisms in SALI has been gradually emphasized. Here, we investigated the effects of a Histone-lysine N-methyltransferase EZH1 (Enhancer of zeste homolog 1) inhibition on promoting ferroptosis resistance to activate nuclear factor, erythroid derived 2, like 2 (NRF2) in SALI. We found that EZH1 deficiency improved animal survival in lethal sepsis. EZH1 deficiency mice exhibited alleviated SALI with decreased hepatocellular ferroptosis. EZH1 deficiency attenuated the H3K27me3 modification in the Nfe2l2 promoter, lending to the increased expression and nuclear translocation of NRF2. In the in vitro, LPS-induced ferroptosis model, EZH1 inhibitor DS3201 exhibited an anti-ferroptosis effect, which was reversed NRF2 inhibitor ML385. These findings indicate that EZH1 deficiency or inhibition with DS3201 alleviates ferroptosis in the liver by activating the NRF2, and it is suggested that targeting EZH1 may be a new therapeutic strategy in SALI.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"96"},"PeriodicalIF":4.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}