Background/Aims Cholangiocarcinoma (CCA) is a primary malignant neoplasm with an extremely poor prognosis. While combined chemoradiotherapy has been demonstrated to delay CCA progression to a certain extent, the absence of specific molecular biomarkers or targets significantly hinders the diagnosis and treatment of CCA.
Methods Through cross-analysis of proteomics and ADMA modificationomics, we identified DDX1 overexpressed in CCA with elevated R602-ADMA modifications. HPLC-MS/MS identified PRMT1 as the methyltransferase and USP10 as the deubiquitinating enzyme for DDX1. Immunofluorescence and nuclear-cytoplasmic partitioning experiments confirmed DDX1’s nuclear localization. GO and KEGG analyses clarify the biological functions of DDX1 in response to hypoxia. RNA-seq transcriptomics analyzed key pathways influenced by DDX1. A hydrodynamic in situ CCA mouse model was established to validate the chemopreventive effects of the PRMT1-specific inhibitor GSK715 on CCA development.
Results DDX1 promotes CCA progression both in vivo and in vitro and can be inhibited by GSK715. Mechanistically, PRMT1 mediates ADMA modification at position R602 of DDX1. This modification promotes DDX1 nuclear localization by recruiting USP10 to deubiquitinate DDX1, while simultaneously inhibiting PRMT1 degradation. DDX1 promotes the transcription of PRMT1 and USP10 by binding to the mRNA 3’UTR region, establishing a positive feedback regulatory pathway. This mechanism promotes the occurrence and development of CCA and can serve as a target for the inhibitor GSK715 to suppress CCA progression.
Conclusions Our study identified DDX1-R602-ADMA modification as a novel ADMA modification in CCA. It further confirmed its pivotal role in CCA progression. Targeting the USP10-PRMT1-DDX1 axis may represent a significant therapeutic approach for CCA.
Hyun Ahm Sohn, Hanyong Go, Tae Hyeon An, Jun Min Lee, Hee-Jin Kim, Keeok Haam, Amal Magdy, Hyo-Jung Jung, Yang-Ji Shin, Hyun Jung Lim, Yujin Jeong, Yejin Bae, Youngae Jung, Seong-Hwan Park, Kyung Chan Park, Myeong Jun Song, Eun-Wie Cho, Eun-Soo Kwon, Jeong Hwan Park, Murim Choi, Geum-Sook Hwang, Dong Hyeon Lee, Kyoung-Jin Oh, Won Kim, Mirang Kim, on behalf of the Innovative Target Exploration of NAFLD (ITEN) Consortium
Clin Mol Hepatol 2026;32(3):1201-1224. Published online January 27, 2026
Background/Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. Aberrant DNA methylation, which is primarily maintained by DNA methyltransferase 1 (DNMT1), has been linked to metabolic dysregulation; however, its contribution to MASLD pathogenesis remains poorly defined. This study aimed to elucidate the role of DNMT1-mediated methylation in transcriptional regulation during MASLD progression and to determine whether DNMT1 inhibition can reverse disease-associated epigenetic and transcriptional alterations.
Methods We conducted integrated analyses of the liver transcriptome (n=131) and DNA methylome (n=106) of patients with biopsy-proven MASLD. We evaluated the effect of DNMT1 inhibition with 5-aza-4′-thio-2′-deoxycytidine (Aza-TdC) on a diet-induced MASLD mouse model. Multiomics approaches, including DNA methylome profiling, lipidomics, RNA sequencing, and chromatin immunoprecipitation sequencing, were applied to elucidate the role of DNMT1-mediated DNA methylation in regulating pathogenic gene expression.
Results DNA methylome profiling revealed increased methylation variability associated with increased DNMT1 expression in MASLD patients. DNMT1 inhibition ameliorated dysregulated lipid metabolism by reducing hepatic triacylglycerol accumulation and inflammation. Aza-TdC treatment partially reversed MASLD-related hypermethylation of hepatocyte nuclear factor 4 alpha (HNF4α)- and peroxisome proliferator-activated receptor alpha (PPARα)-regulated genes, restoring their transcriptional activity. Notably, Aza-TdC reactivated the gluconeogenic enzyme-encoding gene phosphoenolpyruvate carboxykinase 1 (PCK1), which was hypermethylated and transcriptionally repressed in MASLD. Targeted DNA methylation of the PCK1 promoter using CRISPRoff confirmed the direct epigenetic regulation of PCK1 expression.
Conclusions Targeting DNMT1 may mitigate lipid dysregulation and inflammation by reversing hypermethylation and restoring HNF4α- and PPARα-dependent gene transcription, highlighting DNMT1 as a potential therapeutic target for MASLD.
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Background/Aims Hepatitis B virus (HBV) hijacks host cell metabolism, especially host glutamine metabolism, to support its replication. Glutamate dehydrogenase 1 (GDH1), a mitochondrial enzyme crucial for glutamine metabolism, can interact with histone demethylases to regulate gene expression through histone methylation. However, the mechanisms underlying GDH1-mediated glutamine metabolism reprogramming and the roles of key metabolites during HBV infection remain unclear.
Methods Transcriptomic and metabolomic analyses of HBV-infected cell were performed. Both HBV-infected cells and humanized liver chimeric mice were used to elucidate the effect of glutamine metabolism on HBV.
Results HBV infection leads to the abnormal activation of glutamine metabolism, including upregulation of key enzymes and metabolites involved in glutamine metabolism. The viral core protein (HBc) mediates the translocation of GDH1 into the nucleus, where GDH1 activates covalently closed circular DNA (cccDNA) transcription by converting glutamate to α-ketoglutarate (αKG). Mechanistically, the promoting effect of GDH1-derived αKG on cccDNA transcription is independent of its conventional role. Rather, αKG directly interacts with the lysine-specific demethylase KDM4A and enhances KDM4A demethylase activity to regulate αKG-dependent histone demethylation, controlling cccDNA transcription.
Conclusions Our findings highlight the importance of glutamine metabolism in HBV transcription and suggest that glutamine deprivation is a potential strategy for silencing cccDNA transcription.
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Background/Aims Hepatocellular carcinoma (HCC) exhibits high de novo recurrence rates post-resection. Current post-surgery recurrence prediction methods are limited, emphasizing the need for reliable biomarkers to assess recurrence risk. We aimed to develop methylation-based markers for classifying HCC patients and predicting their risk of de novo recurrence post-surgery.
Methods In this retrospective cohort study, we analyzed data from HCC patients who underwent surgical resection in Korea, excluding those with recurrence within one year post-surgery. Using the Infinium Methylation EPIC array on 140 samples in the discovery cohort, we classified patients into low- and high-risk groups based on methylation profiles. Distinctive markers were identified through random forest analysis. These markers were validated in the cancer genome atlas (n=217), Validation cohort 1 (n=63) and experimental Validation using a methylation-sensitive high-resolution melting (MS-HRM) assay in Validation cohort 1 and Validation cohort 2 (n=63).
Results The low-risk recurrence group (methylation group 1; MG1) showed a methylation average of 0.73 (95% confidence interval [CI] 0.69–0.77) with a 23.5% recurrence rate, while the high-risk group (MG2) had an average of 0.17 (95% CI 0.14–0.20) with a 44.1% recurrence rate (P<0.03). Validation confirmed the applicability of methylation markers across diverse populations, showing high accuracy in predicting the probability of HCC recurrence risk (area under the curve 96.8%). The MS-HRM assay confirmed its effectiveness in predicting de novo recurrence with 95.5% sensitivity, 89.7% specificity, and 92.2% accuracy.
Conclusions Methylation markers effectively classified HCC patients by de novo recurrence risk, enhancing prediction accuracy and potentially offering personalized management strategies.
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Clin Mol Hepatol 2024;30(4):824-844. Published online July 25, 2024
Background/Aims Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction–associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD.
Methods Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction–associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing.
Results Methylome and transcriptome analyses of liver biopsies revealed significant (P<0.05) hypermethylation and downregulation of C1R, C1S, C3, C6, C4BPA, and SERPING1, as well as hypomethylation (P<0.0005) and upregulation (P<0.05) of C5AR1, C7, and CD59, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data.
Conclusions Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD.
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Background/Aims RUN×3 (PEBP2αC/CBFA3/AML2) is a novel tumor suppressor gene in the human gastric carcinoma. The aims of this study were to determine the methylation of RUN×3 promoter and the association between RUN×3 methylation and the clinicopathological characteristics of patients with gastric carcinoma. Methods: Seventy-nine patients with gastric carcinoma were studied prospectively from April 2005 to May 2007. The methylations of RUN×3 promoter on the gastric carcinoma specimens and the corresponding nonneoplastic mucosa were evaluated by methylation-specific polymerase chain reaction. Results: Comparison of the results with the clinicopathological characteristics identified RUN×3 monoallelic methylation in 32.9% (26/79) of the gastric carcinoma patients and in 11.4% (9/79) of those with nonneoplastic mucosa (p=0.053). The monoallelic methylated gastric carcinoma specimens predominantly consisted of well- and moderately differentiated carcinomas (44.7%), with the unmethylated group constituting 22.0% of them (p=0.031). Among the 48 patients (60.8%) who underwent gastrectomy, there was no correlation between the two groups with regard to Lauren`s classification (p=0.235), depth of invasion (p=0.990), nodal status (p=0.601), stage (p=0.900), lymphatic invasion (p=0.537), and vascular invasion (p=0.815). Conclusions: Methylation of the tumor suppressor gene RUN×3 might be one of the mechanisms involved in the pathogenesis of gastric carcinoma.
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