Redox ReportPub Date : 2025-12-01Epub Date: 2025-07-16DOI: 10.1080/13510002.2025.2529618
Xinran Liu, Chaoyi Chen, Sai Zhu, Xiaomei Luo, Li Gao, Ziyun Hu, Yu Ma, Ling Jiang, Yonggui Wu
{"title":"ACSF2-PGK1 interaction promotes ferroptosis in renal tubular epithelial cells of diabetic nephropathy by regulating Keap1/Nrf2 signaling.","authors":"Xinran Liu, Chaoyi Chen, Sai Zhu, Xiaomei Luo, Li Gao, Ziyun Hu, Yu Ma, Ling Jiang, Yonggui Wu","doi":"10.1080/13510002.2025.2529618","DOIUrl":"10.1080/13510002.2025.2529618","url":null,"abstract":"<p><strong>Objectives: </strong>Recent studies have highlighted the strong association between kidney disease and ferroptosis. However, the role of ferroptosis in diabetic nephropathy (DN) remains unclear. This study aimed to determine the role of ACSF2 in renal tubule injury in DN and its underlying mechanisms.</p><p><strong>Methods: </strong>We established diabetic kidney disease models both in vivo, using db/db mice, and in vitro, using high glucose induced HK-2 cells.</p><p><strong>Results: </strong>A significant upregulation of ACSF2 was observed in the renal tubules of patients with DN and db/db mice. ACSF2 expression correlated with renal tubule injury and renal function, indicating its potential as an independent biomarker in patients with DN. Silencing ACSF2 alleviated high glucose-induced renal tubular epithelial cell injury by reducing oxidative stress-induced ferroptosis in vivo and in vitro. Mechanistically, liquid chromatography-tandem mass spectrometry and co-immunoprecipitation demonstrated that ACSF2 specifically binds to PGK1. ACSF2 affected Keap1 dimerization by regulating PGK1 phosphorylation at serine 203, which subsequently affects the levels of NRF2. Moreover, PGK1 stabilizes ACSF2 via deubiquitination, establishing a positive feedback loop. The results provide evidence that the interaction between ACSF2 and PGK1 promotes DN progression by regulating oxidative stress-induced ferroptosis.</p><p><strong>Discussion: </strong>ACSF2 participates in crosstalk between oxidative stress and ferroptosis. This could be a potential therapeutic target for DN.</p>","PeriodicalId":21096,"journal":{"name":"Redox Report","volume":"30 1","pages":"2529618"},"PeriodicalIF":5.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12269058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144650221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EpigeneticsPub Date : 2025-12-01Epub Date: 2025-07-14DOI: 10.1080/15592294.2025.2529358
Krishna Priya Ganti, Milan Surjit
{"title":"CpG island demethylation and recruitment of SP1 to the promoter region regulates human thymic stromal lymphopoietin expression.","authors":"Krishna Priya Ganti, Milan Surjit","doi":"10.1080/15592294.2025.2529358","DOIUrl":"10.1080/15592294.2025.2529358","url":null,"abstract":"<p><p>Thymic Stromal Lymphopoietin (TSLP), an immunomodulatory cytokine, plays a pivotal role in the development and progression of atopic and allergic diseases. Atopy follows familial inheritance, and genome-wide studies have shown association of atopy with TSLP polymorphisms. Here, we analysed the conserved transcriptional regulatory elements in the human TSLP promoter, which revealed the presence of three CpG islands. Demethylation of the CpG island using 5-azacytidine or siRNA-mediated knockdown of DNA methyl transferases significantly upregulated TSLP expression. Sequence analysis revealed the presence of two overlapping SP1 transcription factor DNA-binding sites (DBSs), between -1494 and -1510 nucleotides on the human TSLP promoter. Further experiments showed that demethylation of the CpG island enables the binding of SP1 to its cognate DBS present on the TSLP promoter, resulting in its transcriptional activation. Moreover, retinoic acid-induced transcription of human TSLP was associated with CpG island demethylation and SP1 binding to the TSLP promoter. These findings unravel a distinct mechanism of transcriptional regulation of the human TSLP gene and suggest possible epigenetic regulation of TSLP expression in modulating atopic and allergic disease severity in different individuals.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"20 1","pages":"2529358"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12269656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EpigeneticsPub Date : 2025-12-01Epub Date: 2025-07-14DOI: 10.1080/15592294.2025.2530618
Tieshi Zhu, Yong He, Yixi Wang, Le Zhao
{"title":"GrimAge and GrimAge2 Age Acceleration effectively predict mortality risk: a retrospective cohort study.","authors":"Tieshi Zhu, Yong He, Yixi Wang, Le Zhao","doi":"10.1080/15592294.2025.2530618","DOIUrl":"10.1080/15592294.2025.2530618","url":null,"abstract":"<p><p>Epigenetic clocks have been widely applied to assess biological ageing, with Age Acceleration (AA) serving as a key metric linked to adverse health outcomes, including mortality. However, the comparative predictive value of AAs derived from different epigenetic clocks for mortality risk has not been systematically evaluated. In this retrospective cohort study based on 1,942 NHANES participants (median age 65 years; 944 women), we examined the associations between AAs from multiple epigenetic clocks and the risks of all-cause, cancer-specific, and cardiac mortality. Restricted cubic spline models were used to assess the shape of these associations, and Cox proportional hazards regression was employed to quantify risk estimates. Model performance was compared using the Akaike Information Criterion (AIC) and concordance index (C-index). Our findings revealed that only GrimAge AA and GrimAge2 AA demonstrated approximately linear and positive associations with all three mortality outcomes. Both were significantly associated with increased risks of death, and these associations were consistent across most subgroups. GrimAge and GrimAge2 AAs showed very similar performance in predicting all-cause, cancer and cardiac mortality, with only small differences in AIC values and C-index scores. These findings suggest that both GrimAge and GrimAge2 are effective epigenetic biomarkers for mortality risk prediction and may be valuable tools in future ageing-related research.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"20 1","pages":"2530618"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12269703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Isopropyl paraben targets type III secretion to inhibit <i>Salmonella enterica</i> serovar typhimurium infection.","authors":"Jinli Ge, Xueyu Li, Qian Lu, Siqi Li, Jiayang Liu, Xuming Deng, Hongtao Liu, Jiazhang Qiu","doi":"10.1080/21505594.2025.2548621","DOIUrl":"10.1080/21505594.2025.2548621","url":null,"abstract":"<p><p><i>Salmonella enterica</i>, a food- and water-borne pathogen, triggers food poisoning and enteric infections. The effectiveness of antibiotics against <i>Salmonella</i> infections is decreasing due to bacterial resistance. Developing novel antimicrobial agents is crucial and urgent. Here, we screened 550 natural compounds and found that isopropyl paraben (IPPB) effectively inhibited <i>Salmonella enterica</i> serovar Typhimurium (ST) invasion of host cells without impacting bacterial growth, reducing the risk of developing bacterial resistance. Further investigation revealed that IPPB bound to the regulatory protein HilD and inhibited the transcription of the type III protein secretion system 1 (T3SS-1) regulatory genes <i>hilD</i>, <i>hilC</i> and <i>rtsA</i>. This interference blocked the production of T3SS-1 effectors. Importantly, IPPB exerted certain therapeutic effects on both <i>G. mellonella</i> larvae and murine models infected with ST and improved the ST-induced gut microbiota dysbiosis in mice. These findings suggest that IPPB has potential as a novel antimicrobial agent, targeting the T3SS-1 of <i>Salmonella</i>.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":" ","pages":"2548621"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144875460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Effects of <i>Isaria cateniannulata</i> on the colonization process and enzyme activity of <i>Fagopyrum tataricum</i> seeds during germination.","authors":"Xiaona Zhang, Lingdi Gu, Guimin Yang, Can Liu, Kaifeng Huang, Qingfu Chen","doi":"10.1080/21505594.2025.2543062","DOIUrl":"10.1080/21505594.2025.2543062","url":null,"abstract":"<p><p>Endophytic colonization of entomopathogenic fungi has garnered significant attention for its role in promoting plant growth. Specifically, <i>Isaria cateniannulata</i> has shown a positive effect on the germination of <i>Fagopyrum tataricum</i> (buckwheat) seeds, but the mechanisms underlying this promotion remain unclear. This study aims to elucidate the colonization process of <i>I. cateniannulata</i> in <i>F. tataricum</i> seeds during germination stages, quantify the colonization efficiency and tissue specificity of the fungus, and investigate the temporal dynamics of antioxidant enzyme activities and malondialdehyde content triggered by fungal colonization. Furthermore, we evaluated the potential of <i>I. cateniannulata</i>-colonized seedlings to suppress <i>T. urticae</i> populations through oviposition inhibition. The results demonstrated for the first time that <i>I. cateniannulata</i> could successfully colonize germinating <i>F. tataricum</i> seeds during the seed imbibition and germination stages, either by forming dissolution zones with its spores or by germinating and forming mycelia. Initial colonization of all tissues was observed within 16 h, with colonization rates peaking after 5 d, with a preferential colonization rate observed as endosperm > embryo > seed coat. Furthermore, the colonization by <i>I. cateniannulata</i> enhanced peroxidase (POD) activity in the embryo and reduced malondialdehyde (MDA) content. Seedlings grown after colonization were also found to effectively reduce the number of eggs laid by <i>T. urticae</i>. These findings provide both theoretical insights and practical foundations for developing a symbiotic system between <i>I. cateniannulata</i> and <i>F. tataricum</i> seeds.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":" ","pages":"2543062"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12360201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"ASIC1a Promotes nucleus pulposus derived stem cells apoptosis through modulation of SIRT3-dependent mitochondrial redox homeostasis in intervertebral disc degeneration.","authors":"Zhi-Gang Zhang, Liang Kang, Lu-Ping Zhou, Yan-Xin Wang, Chong-Yu Jia, Chen-Hao Zhao, Bo Zhang, Jia-Qi Wang, Hua-Qing Zhang, Ren-Jie Zhang, Cai-Liang Shen","doi":"10.1080/13510002.2025.2504120","DOIUrl":"10.1080/13510002.2025.2504120","url":null,"abstract":"<p><p>The death of human nucleus pulposus derived stem cells (NPSCs) is a key factor affecting the endogenous repair capability and degeneration of intervertebral discs (IVD). ASIC1a is thought to be closely associated with cells destiny in IVD degeneration (IVDD). However, its physiological and pathological roles in human NPSCs are unclear. In this study, we found that the content of ASIC1a increased with IVDD in both rats and human discs. In acidosis-treated NPSCs, the expression level of ASIC1a increased, accompanied by inhibition of cells viability and activation of mitochondrial apoptotic pathway. Additionally, ASIC1a overexpression activated the mitochondrial apoptotic pathway and increased the level of cellular and mitochondrial ROS in human NPSCs. Moreover, we demonstrated that the dysfunction of SIRT3-regulated mitochondrial redox homeostasis was involved in ASIC1a overexpression-induced apoptosis in human NPSCs. The <i>in vivo</i> experiments also demonstrated that the ASIC1a/SIRT3 pathway was involved in IVDD. Overall, these findings showed that ASIC1a disrupted mitochondrial function and aggravated mitochondrial oxidative stress by inhibiting the expression of SIRT3, which activated human NPSC apoptosis and aggravated IVDD. These findings provide new insights for the development of innovative treatment strategies for IVDD.HighlightsAcidosis inhibited human NPSCs activity and promoted apoptosis via mitochondria.ASIC1a promoted acidosis-induced apoptosis of human NPSCs.ASIC1a inhibited SIRT3 expression, aggravating mitochondrial oxidative stress.ASIC1a promoted IVDD via mitochondrial oxidative stress and apoptosis.</p>","PeriodicalId":21096,"journal":{"name":"Redox Report","volume":"30 1","pages":"2504120"},"PeriodicalIF":5.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
VirulencePub Date : 2025-12-01Epub Date: 2025-07-09DOI: 10.1080/21505594.2025.2530166
Haoming Sun, Tingjun Liu, Xuyang Song, Sadiq M S Shah, Qin Zhang, Kerong Shi
{"title":"Identification of fecal microbes as potential biomarkers for early diagnosis of fatty liver disease in cattle.","authors":"Haoming Sun, Tingjun Liu, Xuyang Song, Sadiq M S Shah, Qin Zhang, Kerong Shi","doi":"10.1080/21505594.2025.2530166","DOIUrl":"10.1080/21505594.2025.2530166","url":null,"abstract":"<p><p>Fatty liver disease is prevalent during parturition in dairy cattle. Therefore, there is an urgent need to develop novel, sensitive biomarkers for the early diagnosis of the metabolic disorders. Macroproteomics revealed that the faecal microbial community changes significantly when animal develops fatty liver disease. The microbial changes in cows with severe fatty liver (SFL) were greater than cows with moderate fatty liver (MFL) and normal condition (Norm). This suggests that microorganisms play an important role in the pathogenesis of metabolic disorders. In this study, faeces-sourced microorganisms and microbial proteins were identified and testified as novel biomarkers for the early diagnosis of fatty liver disease in cattle. For example, the AUC (area under curve) values, based on Receiver Operating Characteristics analysis, of using the combination of <i>Lachnoanaerobaculum</i> and <i>Bifidobacterium</i> (at the <i>genus</i> level) to discriminate MFL and SFL animals reached 0.944 and 0.867, respectively, and 0.922 and 0.985, respectively, for the combination of <i>Bifidobacterium pseudolongum</i> and <i>Lachnospiraceae bacterium</i> (at the <i>species</i> level). Interestingly, the differentially expressed microbial proteins are closely related to the identified microorganisms. For example, the majority of the top 20 microbial proteins with significant expression differences were derived from <i>Bifidobacterium pseudolongum</i>. <i>Bifidobacterium pseudolongum</i> was considered a prominent potential biomarker for the diagnosis of metabolic disorders, especially in fatty liver cattle. The results of this study confirm that faecal microbial dysbiosis signatures can serve as a diagnosis biomarker for non-alcoholic fatty liver disease (NAFLD), but also shed light on faecal microbiota transfer (FMT) experiments in treating NAFLD.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2530166"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12247111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
VirulencePub Date : 2025-12-01Epub Date: 2025-07-14DOI: 10.1080/21505594.2025.2532806
Sai Niu, Yian Deng, Yonggen Yang, Junjie Wang, Chunyue Fang, Ying Zhou, Hanchuan Dai
{"title":"A comprehension and systematic insight into the interaction between ferroptosis and virus infection: The implications of mechanisms and strategies.","authors":"Sai Niu, Yian Deng, Yonggen Yang, Junjie Wang, Chunyue Fang, Ying Zhou, Hanchuan Dai","doi":"10.1080/21505594.2025.2532806","DOIUrl":"10.1080/21505594.2025.2532806","url":null,"abstract":"<p><p>Ferroptosis is a novel form of iron-dependent programmed cell death characterized by iron metabolic derangement, an abnormal antioxidant system, and lipid peroxidation. Emerging evidence revealed that viruses modulate ferroptosis to facilitate their replication, dissemination, and pathogenesis, thereby promoting infection or achieving immune evasion by hijacking the host's iron metabolism. However, the interplay between ferroptosis and virus infections remains to be elucidated. This review comprehensively summarizes the core mechanisms of ferroptosis, including iron homeostasis, the system Xc<sup>-</sup>/GPX4 pathway, the FSP1/CoQ10 pathway, lipid peroxidation, and their essential roles were discussed in ferroptosis. We highlighted the relationship between the core mechanisms of ferroptosis and virus infection. Furthermore, we revealed the underlying pathogenic mechanisms of viral infections and the prospective applications targeting ferroptosis. This article is conducive to deepening our understanding of the regulatory mechanism of ferroptosis, unraveling the potential therapeutic intervention and pharmacological direction for the development of innovative ferroptosis-dependent antiviral agents.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2532806"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12269692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Circulated echovirus 18 strains in Guangdong Province and worldwide: A novel perspective on genetic diversity and recombination patterns.","authors":"Zhiyu Li, Xiaohan Yang, Ru Bai, Ping Li, Yanting Qin, Mingyong Luo","doi":"10.1080/21505594.2025.2534519","DOIUrl":"10.1080/21505594.2025.2534519","url":null,"abstract":"<p><p>Echovirus 18 (E18) has re-emerged as a global public health concern in recent years because of its association with severe neonatal systemic diseases that pose a risk of high mortality. The lack of effective intervention strategies for E18 infections is largely attributed to limited knowledge regarding molecular epidemiology and recombination patterns. In this study, we obtained seven full-length E18 sequences from infants in Guangdong Province and combined them with representative sequences from GenBank. Using this expanded dataset, we analysed the molecular epidemiological features, genetic characteristics, and recombination patterns of E18. Global statistics reveal a distinct double-peak pattern in the frequency of E18 infections throughout the year in the Northern Hemisphere. All strains isolated from clinical specimens were classified as genotype C2, which has emerged as the predominant circulating strain in Guangdong Province and globally. Several potential recombination events with E30 were identified among these seven strains, particularly in the P2 and P3 non-structural regions. This study offers new insights into the global dissemination, genetic diversity, and phylodynamics of E18, potentially providing valuable information for designing antiviral vaccines and the implementation of sustainable surveillance strategies to enhance virus prevention and control during public health crises.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":" ","pages":"2534519"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12296116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EpigeneticsPub Date : 2025-12-01Epub Date: 2025-07-07DOI: 10.1080/15592294.2025.2524411
Caitlin Lahue, Eleanor Wong, Aryan Dalal, Wilson Tan Lek Wen, Shuxun Ren, Roger Foo, Yibin Wang, Christoph D Rau
{"title":"Mapping DNA methylation to cardiac pathologies induced by beta-adrenergic stimulation in a large panel of mice.","authors":"Caitlin Lahue, Eleanor Wong, Aryan Dalal, Wilson Tan Lek Wen, Shuxun Ren, Roger Foo, Yibin Wang, Christoph D Rau","doi":"10.1080/15592294.2025.2524411","DOIUrl":"10.1080/15592294.2025.2524411","url":null,"abstract":"<p><p>Heart failure (HF) is a major global health challenge, contributing to over 18 million deaths annually. While the roles of genetic and environmental factors are widely studied, the role of DNA methylation in HF pathogenesis is not fully understood. This study leverages the Hybrid Mouse Diversity Panel (HMDP) to investigate the relationship between DNA methylation, gene expression, and HF phenotypes under isoproterenol-induced cardiac stress. Using reduced representational bisulfite sequencing, we analyzed DNA methylation profiles in the left ventricles of 90 HMDP strains. Epigenome-wide association studies identified 56 CpG loci linked to HF phenotypes, with 18 loci predicting HF progression. Key genes, including Prkag2, Anks1a, and Mospd3, were implicated through integration with gene expression and phenotypic data. In vitro validation confirmed the roles of Anks1aand Mospd3 in attenuating isoproterenol-induced hypertrophy. Additionally, treatment with the DNA methyltransferase inhibitor RG108 mitigated cardiac hypertrophy, preserved ejection fraction, and restored methylation-sensitive gene expression, underscoring the therapeutic potential of targeting DNA methylation in HF. This study highlights the interplay between DNA methylation, gene expression, and HF progression, offering new insights into its molecular underpinnings. The findings emphasize the role of epigenetic regulation in HF and suggest DNA methylation as a promising target for therapeutic intervention.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"20 1","pages":"2524411"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}