Cellular & Molecular Biology Letters最新文献

{"title":"Radiation-sensitive circRNA promotes intestinal regeneration.","authors":"Hui Cai, Xin Liang, Shazhen Ai, Hao Sun, Xinyu Zhang, Qianying Lu, Qingshan Yang, Ying Li, Di Zhao, Manman Zhang, Kaihua Ji, Yan Wang, Qiang Liu","doi":"10.1186/s11658-025-00782-y","DOIUrl":"https://doi.org/10.1186/s11658-025-00782-y","url":null,"abstract":"<p><strong>Background: </strong>The intestine is one of the most sensitive organs to ionizing radiation (IR), and radiation-induced intestinal injury (RIII) impacts the quality of life of patients undergoing radiotherapy. There are limited early diagnostic biomarkers and specific medicines clinically approved for RIII. Therefore, we sought to identify new theranostic targets to prevent RIII and to facilitate the reestablishment of the intestinal epithelium. Circular RNAs (circRNAs) are widely appreciated as pervasive regulators of many diseases and multiple biological processes, while whether and how specific circRNAs are involved in radiation-induced intestinal injury remains largely unknown.</p><p><strong>Methods: </strong>Differentially expressed circRNAs were analyzed and verified via RNA sequencing. The function of an intestine-specific circRNA (termed circDmbt1(3,4,5,6)) on cell proliferation, apoptosis, and DNA damage level after radiation was explored in vitro, and the underlying mechanism was further investigated. Ultimately, intestinal organoids and mice model were used to verify the role of circDmbt1(3,4,5,6) on radiation-induced intestinal injury.</p><p><strong>Results: </strong>Primarily expressed in intestinal stem cells, CircDmbt1(3,4,5,6) was downregulated in mice intestines after 14 Gy abdominal radiation and showed timely relationship with intestinal injury level. CircDmbt1(3,4,5,6) promoted the proliferation and alleviated cell apoptosis and DNA damage level of intestinal epithelial cells and promoted organoids survival after radiation compared with control groups. In vivo experiments showed that compared with control groups, overexpression of circDmbt1(3,4,5,6) could increase intestinal length; enhance epithelial integrity and the percentage of proliferative cells, stem cells, paneth cells, and goblet cells; and promote intestinal adaption after radiation. Mechanistically, circDmbt1(3,4,5,6) protects intestines from IR via circDmbt1(3,4,5,6)/miR-125a-5p/STAT3.</p><p><strong>Conclusions: </strong>CircDmbt1(3,4,5,6), a novel promising RIII bio-marker, responses rapidly at the early stage after 14 Gy abdominal irradiation, and exogenous expression of circDmbt1(3,4,5,6) could promote intestinal fitness in RIII. We reveal that the circDmbt1(3,4,5,6)/miR-125a-5p/STAT3 axis is important to the regeneration of the intestinal epithelium after radiation-induced damage, providing a potential diagnostic and therapeutic target for RIII.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"104"},"PeriodicalIF":10.2,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12395889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944351","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":"Growth differentiation factor 11 attenuates sepsis-associated acute kidney injury by reducing inflammation and coagulation via PGC-1α/Nrf2 activation.","authors":"Hong-Wei Wang, Min-Min Wu, Mian-Mian Zhu, Yu-Ying Qin, Ke-Qi Wang, Chen-Yu Wu, Rong-Rong Zhang, Yin Wang, Chen Zhou, Shuang Luo, Chao-Sheng Lu, Jing-Ye Pan","doi":"10.1186/s11658-025-00762-2","DOIUrl":"https://doi.org/10.1186/s11658-025-00762-2","url":null,"abstract":"<p><strong>Background: </strong>Patients with sepsis commonly endure severe renal dysfunction and damage, hastening to end-stage renal failure with high mortality, and effective treatment options are currently lacking. Growth differentiation factor 11 (GDF11), belonging to the transforming growth factor beta (TGF-β) superfamily, has shown therapeutic potential for numerous acute and chronic inflammatory conditions. Nevertheless, its function in sepsis-associated acute kidney injury (SAKI) remains unclear.</p><p><strong>Purpose: </strong>This study sought to explore GDF11's role in SAKI and determine the signaling pathways it modulates.</p><p><strong>Methods: </strong>Alterations in GDF11 expression in the kidneys of mice with SAKI were analyzed. The influence of GDF11 knockdown and recombinant GDF11 (rGDF11) supplementation on cecal ligation and puncture (CLP)-induced SAKI in mice was determined. RNA sequencing, Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and kit assays were performed to explore the underlying mechanisms.</p><p><strong>Results: </strong>Tubular epithelial cells and macrophages in the kidneys of CLP-induced SAKI mice exhibited high levels of GDF11 expression. Moreover, gene silencing of GDF11 using adeno-associated virus (AAV) aggravated renal dysfunction, increased tubular damage, and augmented renal apoptosis in CLP-induced SAKI mice. In contrast, replenishment of rGDF11 significantly mitigated these adverse effects. Further studies indicated that GDF11 stimulated the nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated antioxidative pathways, primarily by inducing the expression of Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which subsequently decreased excessive inflammation and coagulation. Additionally, these beneficial effects of GDF11 were largely diminished by AAV-mediated PGC-1α knockdown and depletion of Nrf2 in CLP-induced SAKI mice.</p><p><strong>Conclusions: </strong>In summary, these findings indicate that GDF11 is a potential therapeutic approach for SAKI and highlight the crucial role of PGC-1α/Nrf2 signaling in GDF11-mediated renal protection during SAKI.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"102"},"PeriodicalIF":10.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12392574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944279","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":"NSUN2-tRNA^Val-CAC-axis-regulated codon-biased translation drives triple-negative breast cancer glycolysis and progression.","authors":"Wenlong Wang, Ying Ding, Haixi Zhao, Shouman Wang, Juan Huang, Lunquan Sun","doi":"10.1186/s11658-025-00781-z","DOIUrl":"https://doi.org/10.1186/s11658-025-00781-z","url":null,"abstract":"<p><strong>Background: </strong>Epitranscriptomic data indicate that aberrant tRNA modifications in malignant diseases can promote tumor growth by facilitating oncogene translation. NSUN2, a 5-methylcytosine (m5C) methyltransferase of tRNA, is elevated in an array of solid cancers, including triple-negative breast cancer (TNBC). However, it remains unclear how NSUN2 drives aggressive behavior and if NSUN2 could be an effective therapeutic target for TNBC.</p><p><strong>Methods: </strong>Functional experiments, including RNA interference, lentivirus transduction, and in vivo xenograft models, were conducted to evaluate the role of NSUN2 in TNBC cell proliferation, metastasis, and chemoresistance. Ribosome sequencing (Ribo-seq), tRNA m5C bisulfite sequencing, and codon usage bias analysis were employed to explore the translational mechanisms underlying NSUN2-mediated tRNA modifications. Glycolysis assays and molecular docking were used to investigate metabolic reprogramming and protein interactions.</p><p><strong>Results: </strong>NSUN2 was significantly upregulated in TNBC and correlated with poor patient prognosis. Mechanistically, NSUN2 mediates m5C modification of tRNA^Val-CAC, enhancing the codon-frequency-dependent translation of key glycolysis-related genes, including ALDH3A2, ALDH7A1, HK1, and PFKM. Depletion of NSUN2 disrupted tRNA^Val-CAC m5C modification, impairing the translation of these metabolic enzymes and suppressing glycolysis, which ultimately inhibited TNBC cell proliferation, migration, and invasion both in vitro and in vivo. Furthermore, NSUN2 overexpression conferred resistance to docetaxel, while its inhibition sensitized TNBC cells to docetaxel treatment. Clinically, elevated expression levels of NSUN2 and glycolysis-related genes were observed in docetaxel-resistant TNBC tissues, further supporting the role of NSUN2 in chemoresistance.</p><p><strong>Conclusions: </strong>This study identifies NSUN2 as a critical regulator of TNBC progression through tRNA^Val-CAC m5C modification and codon-biased translation of glycolysis-related mRNAs. Our findings reveal a novel NSUN2-tRNA^Val-CAC axis that orchestrates metabolic reprogramming and translational control in TNBC, offering a promising prognostic biomarker and therapeutic target.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"100"},"PeriodicalIF":10.2,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12376479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944320","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":"Hypoxia inducible factor 1α-driven steroidogenesis impacts systemic hematopoiesis.","authors":"Deepika Watts, Nicolas Eberz, Mangesh T Jaykar, Anupam Sinha, Cagdas Ermis, Johanna Tiebel, Ulrike Baschant, Martina Rauner, Tatyana Grinenko, Triantafyllos Chavakis, Peter Mirtschink, Ali El-Armouche, Ben Wielockx","doi":"10.1186/s11658-025-00777-9","DOIUrl":"https://doi.org/10.1186/s11658-025-00777-9","url":null,"abstract":"<p><strong>Background: </strong>Glucocorticoids (GCs) are key regulators of hematopoiesis, but the effects of chronically elevated endogenous GC levels on hematopoietic stem cell (HSC) function and immune cell development remain poorly understood.</p><p><strong>Methods: </strong>We used a mouse model with adrenocortical cell-specific deletion of hypoxia-inducible factor-1 alpha (HIF1α; P2H1^Ad.Cortex), which results in sustained and systemic elevation of GC. Hematopoietic stem and progenitor cell (HSPC) populations were analyzed phenotypically and functionally. Transplantation assays assessed the regenerative capacity of HSCs. To determine the role of glucocorticoid receptor (GR) signaling, bone marrow from GR-deficient or wild-type donors was transplanted into P2H1^Ad.Cortex or wild-type (WT) recipients.</p><p><strong>Results: </strong>Chronic GC exposure in P2H1^Ad.Cortex mice resulted in HSPC expansion and promoted HSC quiescence and metabolic restraint. Functionally, these HSCs showed enhanced regenerative capacity with superior donor chimerism upon transplantation. There was a marked increase in myeloid progenitors and their progeny, including monocytes and granulocytes. In contrast, B-cell development was significantly impaired, with a developmental block at the pre-pro-B-cell stage. Transplantation studies confirmed that these effects were dependent on GR signaling.</p><p><strong>Conclusions: </strong>Our study reveals a critical role for chronic GC-GR signaling in modulating HSC function, promoting myeloid output, and impairing B-cell development. The P2H1^Ad.Cortex mouse model provides a valuable system to study the hematopoietic consequences of prolonged endogenous glucocorticoid exposure and may aid in understanding the hematologic complications of chronic GC therapy.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"101"},"PeriodicalIF":10.2,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944265","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":"Cell death signaling and immune regulation: new perspectives on targeted therapy for sepsis.","authors":"Huang Wu, Jiale Cui, Jie Huang, Yuqi Feng, Jiaxin Zhao, Yalin Zhu, Xiaoming Deng, Xinyu Li, Wangzheqi Zhang, Changli Wang","doi":"10.1186/s11658-025-00784-w","DOIUrl":"10.1186/s11658-025-00784-w","url":null,"abstract":"<p><p>Cell death is essential for the preservation of tissue homeostasis, regulating inflammatory responses, and shaping immune status. The mechanism of cell death includes apoptosis, pyroptosis, necroptosis, ferroptosis and autophagy. The onset, progression, and unfavorable prognosis of sepsis are closely associated with these pathways. Here, the mechanisms associated with these five major cell death pathways in sepsis are reviewed, emphasizing two core aspects of the condition: excessive inflammation and immune suppression. These pathways play a fundamental role in modulating these characteristics and offer novel therapeutic prospects. The study provides valuable insights and detailed analyses, making a significant contribution to ongoing research in this domain. The interconnected nature of cell death is highlighted, not only by examining the distinct roles of individual pathways but also by exploring the interactions between different pathways and the crosstalk among key signaling molecules or pathways, including the caspase family, gasdermin family, and NF-κB pathway. Further research should continue to investigate well-established cell death mechanisms while also identifying previously unknown pathways. Therapeutic strategies targeting cell death pathways hold broad application potential. However, during the transition from preclinical research to clinical application, several challenges remain, including limitations of experimental models, as well as the safety and efficacy of treatments. Additionally, the development of personalized treatment approaches tailored to the unique immune profiles of patients is crucial for advancing precision medicine. In conclusion, the present review offers an extensive analysis of the diverse roles of cell death in sepsis, with novel insights into disease mechanisms and guiding therapeutic developments.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"99"},"PeriodicalIF":10.2,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858965","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":"Palmitoylation: an emerging therapeutic target bridging physiology and disease.","authors":"Weini Li, Jie Shen, Aojia Zhuang, Ruiheng Wang, Quanqi Li, Anas Rabata, Yanan Zhang, DuoYao Cao","doi":"10.1186/s11658-025-00776-w","DOIUrl":"10.1186/s11658-025-00776-w","url":null,"abstract":"<p><p>Palmitoylation is a reversible post-translational lipid modification of proteins, catalyzed by the Zinc finger DHHC domain-containing (ZDHHC) family of palmitoyltransferases. Palmitoylation plays a pivotal role in regulating localization, stability, trafficking, and interactions, thereby contributing to a wide range of cellular processes. Dysregulation of palmitoylation has been implicated in numerous pathological conditions, including metabolic disorders, muscular diseases, mitochondrial disorders, cancer, and neurodegeneration. In this review, we summarize recent advances in understanding S-palmitoylation, emphasizing its critical roles in protein regulation, cellular and physiological processes, and its implications in both health and disease. Additionally, we highlight emerging therapeutic opportunities and novel strategies in therapeutic applications targeting this lipid modification.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"98"},"PeriodicalIF":10.2,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858978","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":"Modeling the effects of radiation on the bone tumor microenvironment: opportunities for exploring combination therapies in microphysiologic systems.","authors":"Kailey N Jackett, Devin L DaPonte, Pranav Soman, Jason A Horton","doi":"10.1186/s11658-025-00774-y","DOIUrl":"10.1186/s11658-025-00774-y","url":null,"abstract":"<p><p>Primary bone tumors and bone metastases represent significant challenges in oncology. Radiotherapy is an important adjuvant treatment for several primary bone and musculoskeletal tumors, as well as for palliative care for metastatic bone lesions. While effective in these applications, patients receiving skeletal radiation face a lifelong risk of fragility fracture at the irradiated sites, among other complications. Damage to bone could be reduced by development of tumor-selective radiosensitizers that would enhance the efficacy of radiotherapy, resulting in reducing the radiation dose delivered to the normal tissues. The creation of bone-selective radioprotection and radio-mitigant strategies that could respectively reduce the magnitude of off-target damage and stimulate functional recovery of the healthy bone microenvironment are warranted. Key barriers to progress in this field include the paucity and inconsistency of data on the skeletal effects of radiotherapy, low throughput and high cost of animal models, reproducibility challenges with in vitro experiments, and poor translational relevance of these models, which may not accurately replicate the human bone-tumor microenvironment. Microphysiological systems (MPS) will accelerate progress in this field by enabling rapid and cost-effective investigation while recapitulating the complexity of the bone-tumor microenvironment to more accurately model the collective response to therapy. Here, we summarize the current knowledge on the transient and long-lasting impacts of radiotherapy and explore opportunities for MPS to streamline and expand our knowledge base. We critically evaluate contemporary model systems, including MPS, and offer suggestions for how these systems can be used to efficiently model the intersection of skeletal radiobiology and bone cancer, and accelerate development of combination therapies.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"97"},"PeriodicalIF":10.2,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854708","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":"M2 macrophage-derived extracellular vesicles protect against abdominal aortic aneurysm by modulating macrophage polarization through miR221-5p.","authors":"Yang Ma, Xiang-Jiu Ding, Si-Yu Lu, Xiao-Fang Huang, Yuan-Yuan Hu, Han Liu, Bin Liu, Ke-Yin Liu, Ming-Xiang Zhang, Hao Wang, Feng Xu, Wei-Dong Qin","doi":"10.1186/s11658-025-00768-w","DOIUrl":"10.1186/s11658-025-00768-w","url":null,"abstract":"<p><strong>Background: </strong>Extracellular vesicles (EVs) derived from M2 macrophages (M2-EVs) play a protective role in the pathogenesis of acute lung injury. However, their roles and mechanisms in abdominal aortic aneurysm (AAA) are unknown.</p><p><strong>Methods: </strong>The effects of M2-EVs in AAA were examined in ApoE^-/- mice with angiotensin II infusion. After M2 macrophages were stimulated with antisense oligonucleotides of miR221-5p (miR221-5p-ASOs), EVs were extracted and administered to mice via the tail vein. In vitro, the primary bone marrow-derived monocytes (BMDMs) were isolated and co-cultured with human aortic endothelial cells (HAECs) in Transwell chambers.</p><p><strong>Results: </strong>M2-EVs significantly reduced AAA incidence and maximal aortic diameters, improved fiber continuity, increased α-SMA, and reduced macrophage infiltration in AAA mice. RNA sequencing revealed that miR221-5p was upregulated in M2-EVs and downregulated in AAA. miR221-5p-ASOs reduced the protection of M2-EVs in AAA mice. M2-EVs induced M2 macrophage polarization, while miR221-5p-ASOs had no effect. Moreover, M2-EVs alleviated oxidative stress and inflammatory responses in HAECs. Mechanistically, miR221-5p bound to poly(ADP-ribose) polymerase 1 (PARP-1) mRNA and reduced PARP-1 expression; PARP-1 was bound to protein phosphatase 1ɑ (PP-1ɑ) and negatively regulated its expression. In vitro experiments showed miR221-5p modulated macrophage polarization through the PARP-1/PP-1ɑ/JNK/c-Jun pathway. Macrophage deletion of PARP-1 inhibited AAA formation and phosphorylation of JNK/c-Jun in mice.</p><p><strong>Conclusions: </strong>miR221-5p in M2-EVs plays a critical role in AAA pathophysiology by modulating macrophage polarization through PARP-1/PP-1ɑ/JNK/c-Jun signaling. M2-EVs and miR221-5p represent promising therapeutic options for AAA.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"96"},"PeriodicalIF":10.2,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815885","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":"Hypoxia-induced genome-wide DNA demethylation by DNMT3A and EMT of cancer cells.","authors":"Biswanath Chatterjee, Pritha Majumder, Chun-Chang Chen, Jing-Ping Wang, Po-Hsuan Su, Hung-Cheng Lai, Ching-Chen Liu, Hsin-Nan Lin, Chen-Hsin A Yu, Hanna S Yuan, Che-Kun James Shen","doi":"10.1186/s11658-025-00775-x","DOIUrl":"10.1186/s11658-025-00775-x","url":null,"abstract":"<p><strong>Background: </strong>Despite the comprehensive advancement in the field of cancer therapeutics, there remains an urgent need to identify new pathophysiological mechanisms that can be targeted in isolation or in combination with existing therapeutic regimens. The epithelial-to-mesenchymal transitions (EMT) induced by hypoxia, cytokines, and growth factors involves acquisition of invasive and migratory properties by cancer cells. Epigenetic alterations of DNA methylations and/or histone modifications cause substantial transcriptomic reprogramming in cancer cells during EMT and metastasis, which can be therapeutically targeted by a thorough understanding of the mutual interactions among the epigenetic processes. Previously, the mammalian DNA methyltransferases (DNMTs) have been shown to possess redox- and Ca⁺⁺- dependent active DNA 5mC demethylation activities in addition to the cytosine methylation activity.</p><p><strong>Methods: </strong>In this study, we have carried out experiments using a range of molecular, cellular, and genome editing approaches including cell culturing, CRISPR/Cas9-editing, si- or sh-RNA-mediated knockdown, quantitative RT-PCR, western blotting, ChIP-qPCR, Na-bisulfite sequencing, EMT and lung colonization assays in conjunction with DNA methylome and DNMT3A ChIP-Seq analyses, RESULTS: We found that active DNA demethylation activity of DNMT3A is essential for hypoxia-induced EMT of the SW480 colon cancer cells, its global genomic DNA demethylation, and promoter DNA demethylation/transcriptional activation of EMT-associated genes including TWIST1 and SNAIL1. DNMT3A also regulates hypoxia-induced HIF-1α binding to and transcriptional activation of the TWIST1 promoter as well as genome-wide DNA demethylation and EMT of breast cancer and liver cancer cells. Mechanistic analysis supports a regulatory model where hypoxia-induced H3K36me3 mark recruits DNMT3A to demethylate CpG in the hypoxia-responsive element (HRE), thereby facilitating HIF-1α binding and activation of the promoters of EMT genes.</p><p><strong>Conclusions: </strong>Altogether, this study has provided the first demonstration of a physiological function of the active DNA demethylation activity of the DNMTs. Equally important, our findings have revealed a missing link between the HIF-1α pathway and the O₂-sensing KDM pathway both of which are known to be essential for a wide set of normal and disease-associated cellular processes. Finally, the active DNA demethylation activity of DNMT3A has now emerged as a new potential target for therapeutic development to prevent EMT and metastasis of cancer cells.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"95"},"PeriodicalIF":10.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12326847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788369","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":"Xanthosine alleviates myocardial ischemia-reperfusion injury through attenuation of cardiomyocyte ferroptosis.","authors":"Yang Xu, Wenfeng Zhou, Zhongguo Fan, Yiwei Cheng, Yujia Xiao, Yu Liu, Xinxin Li, Zhenjun Ji, Yi Fan, Genshan Ma","doi":"10.1186/s11658-025-00766-y","DOIUrl":"10.1186/s11658-025-00766-y","url":null,"abstract":"<p><strong>Background: </strong>Ischemic heart disease remains a leading cause of morbidity and mortality worldwide, with myocardial ischemia-reperfusion (I/R) injury significantly contributing to cardiomyocyte death and poor outcomes post-acute myocardial infarction (AMI). Emerging evidence highlights metabolic changes during myocardial injury, particularly in purine metabolism. This study investigates the protective role of xanthosine (XTS), a purine metabolism intermediate, in alleviating I/R injury.</p><p><strong>Methods: </strong>Neonatal and adult mouse myocardial tissues post-myocardial infarction (MI) were analyzed using untargeted and targeted metabolomics to explore metabolic profiles. The effects of XTS on I/R injury were evaluated in vivo using a murine I/R model and in vitro with hypoxia/reoxygenation-treated neonatal rat cardiomyocytes (NRCMs). Cardiac function, fibrosis, apoptosis, oxidative stress markers, and ferroptosis-related pathways were assessed via echocardiography, biochemical assays, western blotting, and electron microscopy. Integrated drug affinity responsive target stability (DARTS)-based drug target screening and RNA-seq transcriptomic profiling elucidate XTS-mediated mechanisms against I/R injury.</p><p><strong>Results: </strong>Metabolomics revealed distinct differences in purine metabolism between neonatal and adult mice post-MI, with significant XTS accumulation observed in neonatal hearts. In vivo, XTS treatment in adult mice enhanced left ventricular function, reduced fibrosis, and alleviated lipid peroxidation and mitochondrial damage post-I/R injury. In vitro, XTS significantly improved cardiomyocyte viability, reduced oxidative stress, and mitigated ferroptosis by restoring glutathione peroxidase 4 (GPX4) levels and reducing acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) expression. Mechanistically, XTS stabilized metabolic enzymes, upregulated L-arginine and glutathione (GSH) to mitigate reactive oxygen species(ROS), and inhibited ferroptosis.</p><p><strong>Conclusions: </strong>XTS, a key purine metabolism intermediate, improves cardiac remodeling and function following I/R injury by suppressing ferroptosis and reducing mitochondrial ROS production. These findings provide novel insights into the therapeutic potential of XTS as an adjunctive treatment for patients with AMI undergoing revascularization.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"30 1","pages":"93"},"PeriodicalIF":10.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12306105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728279","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}