Cellular & Molecular Biology Letters最新文献

{"title":"Perspectives on mitochondrial dysfunction in the regeneration of aging skeletal muscle.","authors":"Kai Wang, Mailin Gan, Yuhang Lei, Tianci Liao, Jiaxin Li, Lili Niu, Ye Zhao, Lei Chen, Yan Wang, Li Zhu, Linyuan Shen","doi":"10.1186/s11658-025-00771-1","DOIUrl":"10.1186/s11658-025-00771-1","url":null,"abstract":"<p><p>As the global population trends toward aging, the number of individuals suffering from age-related debilitating diseases is increasing. With advancing age, skeletal muscle undergoes progressive oxidative stress infiltration, coupled with detrimental factors such as impaired protein synthesis and mitochondrial DNA (mtDNA) mutations, culminating in mitochondrial dysfunction. Muscle stem cells (MuSCs), essential for skeletal muscle regeneration, also experience functional decline during this process, leading to irreversible damage to muscle integrity in older adults. A critical contributing factor is the loss of mitochondrial metabolism and function in MuSCs within skeletal muscle. The mitochondrial quality control system plays a pivotal role as a modulator, counteracting aging-associated abnormalities in energy metabolism and redox imbalance. Mitochondria meet functional demands through processes such as fission, fusion, and mitophagy. The significance of mitochondrial morphology and dynamics in the mechanisms of muscle regeneration has been consistently emphasized. In this review, we provide a comprehensive summary of recent advances in understanding the mechanisms of aging-related mitochondrial dysfunction and its role in hindering skeletal muscle regeneration. Additionally, we present novel insights into therapeutic approaches for treating aging-related myopathies.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"94"},"PeriodicalIF":10.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12305941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FLNA, a disulfidptosis-related gene, modulates tumor immunity and progression in colorectal cancer.","authors":"Qiong Li, Renhong Huang, Lingling Lv, Haifeng Ying, Yuan Wu, YuQing Huang, Yuxi Li, Wen Ma, Xiaoshuang Liu, Qinghui Meng, Fengying Xing, Yan Shen, Lan Zheng","doi":"10.1186/s11658-025-00761-3","DOIUrl":"10.1186/s11658-025-00761-3","url":null,"abstract":"<p><strong>Background: </strong>Disulfidptosis represents a novel type of regulated cell death induced by excessively high intracellular levels of cystine. Targeting disulfide imbalance is considered a promising treatment approach for colorectal cancer (CRC). However, the involvement of disulfidptosis in CRC immunotherapy is undefined.</p><p><strong>Methods: </strong>Unsupervised clustering was applied to The Cancer Genome Atlas (TCGA) datasets to classify disulfidptosis-related phenotypes. The tumor microenvironment (TME) was characterized using diverse bioinformatics algorithms, including gene set variation analysis (GSVA) for pathway enrichment analysis and CIBERSORT for immune cell profiling. A disulfidptosis-related gene (DRG) signature was generated for stratifying CRC cases, and univariate Cox regression was utilized for identifying prognostic DRGs. Filamin A (FLNA) was pinpointed as a pivotal regulator of disulfidptosis, and its functional impacts on tumor progression and immunotherapy response were further investigated.</p><p><strong>Results: </strong>Two different groups were determined on the basis of the built disulfidptosis-related signature (DRS), showing distinct clinical outcomes, as well as different pathway activation, drug sensitivity, and immune infiltration patterns. The high-DRS subgroup correlated with poorer prognosis, elevated immunosuppressive cell activity, and reduced cytotoxic immune cell infiltration. FLNA emerged as a critical mediator of disulfidptosis in CRC, with its knockdown suppressing tumor cell migration and invasion in vitro. The FLNA inhibitor PTI-125 attenuated tumor growth and epithelial-mesenchymal transition (EMT), while FLNA depletion reversed glucose-driven metastasis. Notably, combined glucose transporter 1 (GLUT1) inhibition and anti-programmed cell death protein 1 (PD-1) therapy enhanced CD8⁺ T cell recruitment and suppressed EMT.</p><p><strong>Conclusions: </strong>This study elucidates the interplay between disulfidptosis and the CRC immune landscape, highlighting FLNA as a therapeutic target. These findings suggest that modulating disulfidptosis in conjunction with immunotherapy may offer a novel treatment paradigm for CRC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"92"},"PeriodicalIF":10.2,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms and functions of protein acetylation in sepsis and sepsis-associated organ dysfunction.","authors":"Yang-Fan Xu, Ni Yang, Peng-Hui Hao, Ri Wen, Tie-Ning Zhang","doi":"10.1186/s11658-025-00773-z","DOIUrl":"10.1186/s11658-025-00773-z","url":null,"abstract":"<p><p>Sepsis, a life-threatening condition characterized by organ dysfunction due to dysregulated host response to infection, remains a global health challenge with high morbidity, mortality, and long-term sequelae. The development of sepsis-associated organ dysfunction (SAODs) substantially worsens prognosis. Despite extensive studies, the pathophysiological mechanisms underlying sepsis and SAODs remain unclear. Protein acetylation is a widespread and reversible post-translational modification regulated by acetyltransferases and deacetylases that occurs on both histone and non-histone proteins. This modification plays a critical role in modulating various cellular processes by modifying target proteins. Emerging evidence indicates that acetylation is involved in sepsis and SAODs through regulation of key biological processes. In this review, we discuss the regulatory enzymes and mechanisms of acetylation, highlight their roles in sepsis and associated organ dysfunction, and explore the potential of acetylation modulators as therapeutic agents, offering new insights into understanding sepsis and developing novel therapeutic strategies.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"91"},"PeriodicalIF":10.2,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune factors and their role in tumor aggressiveness in glioblastoma: Atypical cadherin FAT1 as a promising target for combating immune evasion.","authors":"Manvi Arora, Archismita Kundu, Subrata Sinha, Kunzang Chosdol","doi":"10.1186/s11658-025-00769-9","DOIUrl":"10.1186/s11658-025-00769-9","url":null,"abstract":"<p><p>Immune evasion is one of the hallmarks of cancers, including glioblastoma, the most aggressive form of primary brain tumors. Multiple mechanisms are employed by tumor cells and its microenvironment to evade immune detection and foster tumor growth and progression. The secretion of immunosuppressive molecules such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), the expression of checkpoint proteins such programmed death-ligand 1 (PD-L1), and the recruitment of T-regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) leads to suppressed immune cell activity, favoring unchecked tumor growth. The FAT atypical cadherin 1 (FAT1) has shown context/tissue-dependent effects in cancers of different tissue origins, with either oncogenic or tumor suppressor roles. Our laboratory has reported FAT1 to have an oncogenic function in glioblastoma. In addition, FAT1 promotes an immunosuppressive microenvironment in glioblastoma, reducing T-cell and monocyte infiltration while increasing immunosuppressive cells such as MDSCs. It also upregulates pro-inflammatory mediators [cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and interleukin-6 (IL-6)], fostering tumor-promoting signaling. This dual role in immune evasion and pro-tumorigenic inflammatory processes makes FAT1 a key driver of glioblastoma progression. This highlights the potential of FAT1 as a compelling therapeutic target. This article provides a concise overview of immune tolerance mechanisms in glioblastoma, and the crucial role of FAT1 in promoting immune tolerance and tumor advancement. In addition, this review highlights currently available immunotherapies in clinical use or undergoing trials, and the potential of FAT1 as a promising target for combinatorial therapeutic interventions.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"89"},"PeriodicalIF":10.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NT2-derived astrocyte-neuron co-culture reflects physiological relevance and offers research validity.","authors":"Sylwia Kedracka-Krok, Ewelina Fic, Zuzanna Cepil, Piotr Rybczyński, Agata Szlaga, Radosław Cacała, Sławomir Lasota, Anna Blasiak, Marta Dziedzicka-Wasylewska","doi":"10.1186/s11658-025-00765-z","DOIUrl":"10.1186/s11658-025-00765-z","url":null,"abstract":"<p><strong>Background: </strong>Obtaining human neurons and astrocytes for in vitro studies presents a significant challenge owing to the complexity of replicating their development and functionality outside the human brain. The Ntera-2 cell line is a valuable source of human neurons and astrocytes in neuroscience research. However, differentiating Ntera-2 cells into neurons and astrocytes with all-trans retinoic acid is complicated by the lack of reliable markers to monitor differentiation stages effectively. This study aimed to characterize neuron-enriched and pure astrocyte cultures at two maturation stages and to compare these with the original Ntera-2 cells. Ntera-2 cells and NT2 cells are used interchangeably in this publication.</p><p><strong>Methods: </strong>Using an advanced proteomic approach, we assessed the protein composition and abundance of neuron and astrocyte co-cultures and discovered that the astrocytic protein profile in co-culture with neurons was more representative compared with that in pure astrocyte cultures. Additionally, electrophysiological studies were conducted to investigate the best astrocyte content for neuronal functionality.</p><p><strong>Results: </strong>Mass spectrometry-based analysis provided insights into over 9000 proteins, covering well-known protein markers, proteins unique to specific cell types, and differentially expressed proteins. Notably, differences in transcription factors, regulatory proteins, intermediate filaments, and proteins unique to early and mature astrocytes highlighted the distinct maturation, activation, and functional profiles of the various cells. These findings offer a straightforward tool for characterization and monitoring the differentiation process. Three weeks of maturation in pure culture yielded immature astrocytes; however, extending the maturation period to 6 weeks significantly altered the composition of the cellular proteome, indicating increased astrocyte maturity. Studies revealed a broader repertoire of astrocytic proteins in co-culture with neurons. Meanwhile, electrophysiological analyses demonstrated that a high content of astrocytes is essential for neuronal functional maturity.</p><p><strong>Conclusions: </strong>Astrocyte-neuron co-cultures offer a more accurate model of neural tissue than pure cultures, highlighting the complexity of cell maturation and providing insights for improving in vitro modeling of human neural development.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"90"},"PeriodicalIF":10.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive analysis of keloid super-enhancer networks reveals FOXP1-mediated anti-senescence mechanisms in fibrosis.","authors":"Hao Yang, Dongming Lv, Xiaohui Li, Yongfei Chen, Hailin Xu, Honglin Wu, Zhiyong Wang, Xiaoling Cao, Bing Tang, Wuguo Deng, Jiayuan Zhu, Zhicheng Hu","doi":"10.1186/s11658-025-00763-1","DOIUrl":"10.1186/s11658-025-00763-1","url":null,"abstract":"<p><p>There is a significant gap in multi-omics studies on keloids, especially concerning the interaction between fibroblasts and super-enhancers (SEs). Identifying novel biomarkers within the epigenetic landscape could greatly improve keloid management. In this study, we investigated gene expression at both transcriptional and translational levels to identify potential biomarkers and employed CUT&Tag technology to validate SE-associated genes and upstream transcription factors (TFs). Through integrated analyses of transcriptomics and proteomics, 10 hub genes that associated with ECM, immune, and metabolic pathways were found. Given the crucial role of fibroblasts in keloid pathogenesis, we further identified five SE-associated genes (SERPINH1 SE, MMP14 SE, COL5A1 SE, COL16A1 SE, and SPARC SE) that exhibit characteristic upregulation in keloids. Analysis of upstream TFs and core transcription regulatory circuitry (CRC) revealed potential master TFs (FOSL2, BACH2, and FOXP1), with FOXP1 emerging as the core TF likely driving pro-fibrotic development through its anti-senescence function. In summary, we anticipate that the outcomes of the integrative omics analysis will facilitate further investigation into the underlying molecular mechanisms of keloid formation and lead to novel strategies for its prevention and management. Specifically inhibiting the anti-senescence function of FOXP1 brings new promise for the treatment of fibrosis-related diseases.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"88"},"PeriodicalIF":9.2,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated transcriptomics and metabolomics confirms the oxidative stress mechanism of hypothermia-induced neuronal necroptosis.","authors":"Song-Jun Wang, Chao-Long Lu, Fu Zhang, Xue-Tong Dong, Xiao-Rui Su, Jing-Jing Sha, Bin Cong, Xia Liu","doi":"10.1186/s11658-025-00772-0","DOIUrl":"10.1186/s11658-025-00772-0","url":null,"abstract":"<p><p>Abnormal climate change seriously endangers the safety of outdoor work and life, often causing hypothermia-induced coma or death. As the underlying mechanism has not been fully elucidated, a targeted treatment for hypothermia-triggered neuronal injury and forensic pathology indicators of fatal hypothermia are lacking. Herein, we aimed to explore hypothermia-induced changes in gene expression and metabolite profiles of cerebral cortical tissues to elucidate the mechanism of hypothermia-promoted necroptosis of cerebral cortical neurons. Flow cytometry and fluoro-jade C staining showed that low temperature caused necroptosis of cerebral cortical neurons. Transcriptomics identified 244 differential genes between hypothermia-exposed cortical tissue and control tissue. These genes were enriched in tumor necrosis factor (TNF)-α and nuclear factor (NF)-kappa B signaling pathways, as revealed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Broadly targeted metabolomics identified 49 differential metabolites with significant differences. N-alpha-acetyl-L-arginine, argininosuccinic acid, glutaric acid, and other ornithine cycle-associated metabolites were significantly reduced in the hypothermia-exposed cortical tissue, driving fumaric acid reduction in the tricarboxylic acid (TCA) cycle. In addition, KEGG enrichment analysis showed significant changes in the TCA cycle pathway. A combined transcriptomic and metabolomic analysis uncovered that hypothermia induced oxidative stress through NF-κB activation, caused mitochondrial damage, impaired the ornithine cycle, and, ultimately, induced neuronal necroptosis. Pharmacological inhibition of NF-κB by the SC75741 inhibitor effectively ameliorated hypothermia-triggered necroptosis. In conclusion, our results suggest that the NF-κB transcription factor is a potential marker of hypothermia-induced neuronal necroptosis in the mouse cerebral cortex. In addition, our findings indicate the mechanism of necroptosis in cerebral cortical neurons caused by low temperature, which is beneficial for our understanding of hypothermia-induced coma and death.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"87"},"PeriodicalIF":9.2,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting LINC02320 prevents colorectal cancer growth via GRB7-dependent inhibition of MAPK signaling pathway.","authors":"Lingwei Zhang, Hong Chen, Yangmei Yang, Liangbo Zhao, Huimin Xie, Peixian Li, Xinrui Lv, Luyun He, Nian Liu, Benyu Liu","doi":"10.1186/s11658-025-00770-2","DOIUrl":"10.1186/s11658-025-00770-2","url":null,"abstract":"<p><strong>Background: </strong>It is estimated that over 85% of human transcripts are non-coding RNAs, which play an important role in the regulation of numerous biological processes and are closely associated with the development of human cancers. Nevertheless, the functions of the vast majority of non-coding RNAs are yet to be clearly elucidated.</p><p><strong>Methods: </strong>Long non-coding RNA (lncRNA) LINC02320 was screened out by RNA-sequencing using paired CRC samples. The level of LINC02320 in colorectal cancer (CRC) tissues and cell lines was validated by qRT-PCR and in situ hybridization (ISH). CCK8, colony formation, transwell, wound healing and xenograft experiments were carried out to investigate the function of LINC02320. Antisense oligonucleotide (ASO) was used to target LINC02320. Mass spectrometry, pull-down, western blot and CUT&Tag assays were conducted to investigate the molecular mechanism of LINC02320, ILF2, GRB7, MAPK and FOS.</p><p><strong>Results: </strong>LINC02320 was highly expressed in metastatic colorectal cancer (CRC) tissues based on RNA-sequencing. ISH staining using tissue microarray (TMA) indicated that LINC02320 is associated with the clinical stage and survival rate of patients with CRC. The results of loss-of-function and gain-of-function experiments demonstrated that LINC02320 facilitates cancer cell proliferation and metastasis in vitro and in vivo while simultaneously inhibiting apoptosis. LINC02320 is present in both the nucleus and cytoplasm, with a nuclear function. Mechanistically, LINC02320 recruits the transcriptional regulator ILF2 to the GRB7 promoter, thereby initiating its transcription. GRB7 then activates the mitogen-activated protein kinase (MAPK) signaling pathway, which contributes to CRC progression and leads to increased phosphorylation of the transcription factor FOS. Phosphorylated FOS directly promotes LINC02320 transcription, forming a positive feedback loop and amplifies this pro-cancer signal. Notably, LINC02320-targeted ASO therapy significantly blocked tumor growth in vivo.</p><p><strong>Conclusion: </strong>In summary, our findings demonstrate the essential role of LINC02320 involved in CRC progression, which provides novel insights into the importance of lncRNA as a therapeutic target in cancer treatment.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"86"},"PeriodicalIF":9.2,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: CDC20 protects the heart from doxorubicin-induced cardiotoxicity by modulating CCDC69 degradation.","authors":"Zhenyu Feng, Ningning Zhang, Liang Wang, Xumin Guan, Yunpeng Xie, Yun-Long Xia","doi":"10.1186/s11658-025-00767-x","DOIUrl":"10.1186/s11658-025-00767-x","url":null,"abstract":"","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"85"},"PeriodicalIF":9.2,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12276703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPD2 inhibition impairs coagulation function via ROS/NF-κB/P2Y12 pathway.","authors":"Jiajie Chen, Guifeng Xu, Zhipeng Xie, Shaoxia Xie, Wenwei Luo, Shilong Zhong, Weihua Lai","doi":"10.1186/s11658-025-00759-x","DOIUrl":"10.1186/s11658-025-00759-x","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Coronary heart disease (CHD) remains a global health threat. As antiplatelet therapy constitutes the cornerstone of CHD management, ticagrelor has been universally endorsed as a first-line agent in major clinical guidelines. However, the therapeutic efficacy of ticagrelor is compromised by interindividual variability in bleeding risk. Notably, while inherited genetic variations account for part of this heterogeneity, the dynamic regulatory role of modifiable epigenetic mechanisms-particularly DNA methylation in mediating platelet reactivity-remains inadequately characterized, presenting a critical knowledge gap in optimizing precision antiplatelet strategies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We utilized the 850k methylation array to measure DNA methylation levels in blood samples from 47 healthy controls and 93 patients with CHD. Subsequently, epigenome-wide association study (EWAS), summary data-based Mendelian randomization (SMR), and heterogeneity in dependent instruments (HEIDI) analyses were applied to pinpoint critical methylation sites that influence gene expression, platelet function recovery, and bleeding risk. After developing a targeted cellular model using the CRISPR-dCas9-DNMT3A/Tet1CD-U6-sgRNA system and integrating with transcriptomic sequencing data, we conducted mechanistic cellular experiments to elucidate how these methylation sites affect platelet function recovery and bleeding risk. The findings were further validated through animal studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Integrated analysis of EWAS and SMR-HEIDI revealed that hypermethylation at CpG site cg03230175 within the GPD2 gene promoter region was significantly associated with decreased GPD2 gene expression (P = 1.76E-18), delayed platelet functional recovery (P = 9.02 × 10&lt;sup&gt;-3&lt;/sup&gt;), and elevated hemorrhagic risk (P = 2.71 × 10&lt;sup&gt;-2&lt;/sup&gt;). Transcriptomic studies indicated that GPD2 gene (cg03230175) methylation affects mitochondrial function, nuclear factor kappa B (NF-κB) signaling pathway, reactive oxygen species metabolic process, and G protein-coupled receptor (GPCR) ligand binding. Cellular experiments demonstrated that the GPD2 gene (cg03230175) methylation inhibits coagulation function by suppressing reactive oxygen species (ROS) production, NF-κB activation, and P2Y12 gene expression (P2Y12 receptor plays a pivotal role in platelet activation, thrombus formation, and the pathogenesis of thrombotic disorders). The animal study results confirmed that GPD2 enzyme inhibition can indeed prolong the clotting time in mice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;GPD2 gene (cg03230175) methylation resulted in reduced gene expression levels, inhibited mitochondrial energy metabolism, decreased ROS levels, and affected P2Y12 gene expression through the NF-κB pathway, ultimately leading to inhibition of coagulation function. Registry: The Impact of Genotype on Pharmacokinetics and Antiplatelet Effects of Ticagrelor in Healthy Chinese ","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"84"},"PeriodicalIF":9.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}