Experimental and Molecular Medicine最新文献

{"title":"METTL1-driven epitranscriptomic enhancement of TXNDC12 boosts c-Myc stability through USP5 in HNSCC.","authors":"Zizhao Mai, Jiarong Zheng, Ye Lu, Pei Lin, Yunfan Lin, Yucheng Zheng, Xu Chen, Bing Guo, Li Cui, Xinyuan Zhao","doi":"10.1038/s12276-025-01512-2","DOIUrl":"https://doi.org/10.1038/s12276-025-01512-2","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy worldwide. Advancing understanding of the molecular mechanisms driving tumor progression and resistance to therapy is essential for developing new strategies to improve patient outcomes in HNSCC. Here we demonstrate that elevated expression of thioredoxin domain-containing protein 12 (TXNDC12) in HNSCC is associated with adverse clinical outcomes and reduced survival. Modulating TXNDC12 levels demonstrates that its reduction curtails aggressive tumor phenotypes and cisplatin resistance, while its overexpression exacerbates these characteristics. Comprehensive RNA transcriptomic analysis reveals that depletion of TXNDC12 leads to significant suppression of c-Myc signaling pathways. Mechanistically, TXNDC12 stabilizes c-Myc protein by promoting its interaction with USP5, thus preventing proteasomal degradation of c-Myc. Moreover, METTL1 enhances TXNDC12 mRNA stability via an m⁷G-dependent mechanism. Clinical validation underscores the importance of the METTL1-TXNDC12-c-Myc axis in HNSCC. Our findings reveal that METTL1-coupled epitranscriptomic upregulation of TXNDC12 in HNSCC enhances c-Myc signaling by promoting its USP5-mediated stability.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicle-mediated delivery of circp53 suppresses the progression of multiple cancers by activating the CypD/TRAP/HSP90 pathway.","authors":"Xichao Yu, Pinggang Ding, Mengjie Guo, Xiaozhu Tang, Ze Wang, Yuanjiao Zhang, Lianxin Zhou, Xinyu Lv, Hui Shi, Hongming Huang, Jialei Mao, Zhancheng Gu, Chunyan Gu, Ye Yang","doi":"10.1038/s12276-025-01506-0","DOIUrl":"https://doi.org/10.1038/s12276-025-01506-0","url":null,"abstract":"<p><p>The majority of cancers remain incurable due to limited therapeutic responses in malignancies with high-risk genetic mutations such as TP53. Building on the success of mRNA vaccine technology, we investigated circular RNA (circRNA) therapeutics and identified hsa_circp53_0041947, a TP53-derived circRNA in multiple myeloma (MM). The hsa_circp53_0041947 encodes a functional peptide (circp53-209aa) demonstrating p53 mutation-independent anti-MM effects through CypD/TRAP1/HSP90 complex-mediated mechanisms. Specifically, circp53-209aa activated cyclophilin D (CypD) isomerase activity at the circp53-209aa-R175 site, triggering mitochondrial permeability transition pore opening and subsequent mitochondrial apoptosis. To enable targeted delivery, we engineered extracellular vesicle (EV) systems, E7-Lamp2b-EVs and Her2-Lamp2b-EVs, for MM and colorectal cancer, respectively. Circp53-EVs administration achieved tumor-selective growth inhibition in both malignancies. Our study establishes engineered circp53-EVs as a versatile therapeutic platform, demonstrating the translational potential of circRNA-based strategies for refractory cancers with TP53 pathway alterations.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Poly(ADP-ribose) polymerase 1 orchestrates vascular smooth muscle cell homeostasis in arterial disease.","authors":"Wenjing Xu, Yichen Wu, Ruiqi Mao, Yujie Jia, Hao Jiang, Fengxiao Zhang, Dan Huang, Ximiao He, Cheng Wang, Kai Huang","doi":"10.1038/s12276-025-01501-5","DOIUrl":"https://doi.org/10.1038/s12276-025-01501-5","url":null,"abstract":"<p><p>Smooth muscle cells are remarkably plastic. Their reversible differentiation is required for growth and wound healing but also contributes to pathologies such as atherosclerosis and restenosis. Here we demonstrate the role of poly(ADP-ribose) polymerase 1 (PARP1) as a critical master regulator of vascular smooth muscle cells (VSMC) plasticity. A robust activation of PARP1 in VSMCs was observed in artery stenosis and atherosclerotic plaques of rodents and human. Inhibition or deletion of PARP1 suppressed the VSMC phenotype switch in vivo and in vitro. Further analysis identified myocardin and myocardin-associated serum response factor as substrates of PARP1-mediated poly(ADP-ribosyl)ation reaction. Poly(ADP-ribosyl)ation of myocardin and serum response factor dissociated the complex from CArG motif in the target promoter and then transcriptionally suppressed contractile protein expression. Moreover, we demonstrated that c-Jun mediated the stimulation of VSMC proliferation and migration by PARP1. Notably, interaction with myocardin is an important mechanism repressing c-Jun transcriptional activity in VSMCs. Poly(ADP-ribosyl)ation of myocardin and c-Jun disrupted myocardin-c-Jun interaction and abolished this repression to promote c-Jun transactivation and target gene expression, thus stimulating VSMC proliferation and migration. Our data reveal that activation of PARP1 not only suppresses contractile status but also promotes the synthetic proliferative phenotype of VSMCs, indicating a pivotal role for PARP1 in determining the phenotype of VSMCs. Targeting PARP1 may hold therapeutic potential for vascular pathologies.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tracking clonal dynamics of CD8 T cells and immune dysregulation in progression of systemic lupus erythematosus with nephritis.","authors":"Seung-Jun Paek, Hye-Soon Lee, Ye Ji Lee, So-Young Bang, Dongju Kim, Bo-Kyeong Kang, Dae Jin Park, Young Bin Joo, Mimi Kim, Hyunsung Kim, Sung Yul Park, Woong-Yang Park, Tatsuki Abe, Takahiro Itamiya, Yasuo Nagafuchi, Kazuyoshi Ishigaki, Keishi Fujio, Kyu-Tae Kim, Sang-Cheol Bae","doi":"10.1038/s12276-025-01504-2","DOIUrl":"https://doi.org/10.1038/s12276-025-01504-2","url":null,"abstract":"<p><p>The fluctuating nature of disease activity in systemic lupus erythematosus (SLE), alternating between flares and remissions, poses substantial challenges for its effective management. The use of current biomarkers for monitoring SLE is limited in clinical settings owing to insufficient comprehension of the complex immune involvement underlying the disease course. Here, therefore, we profiled peripheral blood mononuclear cells at both stable and exacerbation states (total of n = 19) from six patients with SLE and 32 healthy donors using integrated single-cell RNA and T cell receptor (TCR) sequencing. To validate our findings, we analyzed two independent external datasets: bulk RNA sequencing and TCR data from 79 controls and 62 patients with SLE and single-cell RNA sequencing data from 99 healthy controls and 162 patients with SLE. Our analysis revealed cell type-specific activation of interferon-related genes in SLE grouped into four clusters, with elevated activity in disease-associated immune cells. Among these, atypical B cells associated with autoantibody production exhibited distinct differentiation patterns compared with conventional memory B cells, driven by heightened interferon signaling in SLE. Notably, clonal expansion of effector CD8 T cells emerged as a key driver of disease exacerbation, as indicated by reduced TCR diversity. Specific CD8 T cell clonotypes expanded during flare states, transitioning to effector phenotypes that exhibited heightened cytotoxicity and amplified interferon signaling, strongly correlating with tissue damage and flare severity. Our findings establish a critical link between interferon-driven mechanisms and cytotoxic T cell dysfunction in SLE flares, offering potential targets for therapeutic intervention and predictive biomarkers.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatocyte KCTD17-mediated SERPINA3 inhibition determines liver fibrosis in metabolic dysfunction-associated steatohepatitis.","authors":"Yelin Jeong, Ah-Reum Oh, Young Hoon Jung, Kyung Hee Jung, Seongju Lee, Michele Carrer, Sang Bae Lee, Luca Valenti, Utpal B Pajvani, KyeongJin Kim","doi":"10.1038/s12276-025-01499-w","DOIUrl":"https://doi.org/10.1038/s12276-025-01499-w","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease. Available therapies show inconsistent results on fibrosis, probably due to heterogeneity in disease trajectory or incomplete understanding of molecular determinants. Here we identified increased KCTD17 levels in patients with MASH, and in dietary rodent models of MASH-such as those fed a diet high in palmitate, sucrose and cholesterol coupled with fructose-containing drinking water or a choline-deficient, L-amino acid-defined, high-fat diet-which showed an inverse correlation with the expression of serine protease inhibitor a3k (SERPINA3 in humans, Serpina3k in mice). KCTD17 depletion increased SERPINA3 levels and reduced liver fibrosis in mice fed a MASH-inducing diet by inhibiting Par2/TGFβ-mediated activation of hepatic stellate cells. Mechanistically, Kctd17 regulates Serpina3k expression by facilitating the ubiquitin-mediated degradation of Zbtb7b, which in turn diminishes Serpina3k secretion. Consequently, pharmacological inhibition of Kctd17 effectively reverses MASH-induced liver fibrosis. In summary, these findings underscore the therapeutic potential of targeting KCTD17 for the treatment of MASH-induced liver fibrosis.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Canonical Wnt signaling regulates Mbd3 protein stability during neurogenesis.","authors":"Nhu Thi Quynh Mai, Soyoung Jeon, Byoung-San Moon","doi":"10.1038/s12276-025-01510-4","DOIUrl":"https://doi.org/10.1038/s12276-025-01510-4","url":null,"abstract":"<p><p>Acquisition of neural progenitor cell (NPC) homeostasis through balancing self-renewal and differentiation is essential for brain development and function. Among the mechanisms controlling these processes, canonical Wnt signaling and the Mbd3-NuRD complex, with prominent suppressive effects on neurogenesis, have been described as crucial parts of the core regulatory circuit. Here we explored Mbd3 as a downstream element of the canonical Wnt signalosomes. Specifically, dynamic modulation of Wnt signaling through activator (Wnt3a) and inhibitor (DKK1) resulted in parallel alterations in β-catenin and Mbd3 expression patterns. Also, overexpression and depletion of GSK3β respectively promoted and attenuated Mbd3 ubiquitination, highlighting that the canonical Wnt cascade promotes Mbd3 stability. Downstream of the Wnt-β-catenin pathway, Mbd3 represses transcription of neurogenesis-associated genes by triggering NuRD complex assembly, thereby promoting NPC stemness. This new Wnt-Mbd3 axis extends the current understanding of the canonical Wnt network in directing neuronal cell-fate determination in NPCs, suggesting this pathway as a potential target for driving neural stem cell reprogramming and neuronal lineage commitment.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR-based functional genomics tools in vertebrate models.","authors":"Gaurav K Varshney, Shawn M Burgess","doi":"10.1038/s12276-025-01514-0","DOIUrl":"https://doi.org/10.1038/s12276-025-01514-0","url":null,"abstract":"<p><p>The advent of CRISPR-Cas technologies has revolutionized functional genomics by enabling precise genetic manipulations in various model organisms. In popular vertebrate models, including mice and zebrafish, CRISPR has been adapted to high-throughput mutagenesis workflows, knock-in alleles and large-scale screens, bringing us closer to understanding gene functions in development, physiology and pathology. The development of innovative technologies, such as base editors, capable of single-nucleotide modifications, and prime editors, offering precision edits without double-strand breaks, exemplifies the expanding toolkit. In addition to gene editing, transcriptional modulation, that is, CRISPR interference and CRISPR activation systems, can elucidate the mechanisms of gene regulation. Newer methods, such as MIC-Drop and Perturb-seq, which increase screening throughput in vivo, hold significant promise to improve our ability to dissect complex biological processes and mechanisms. Furthermore, CRISPR-based gene therapies for treating sickle cell disease and other monogenic diseases have already demonstrated their potential for clinical translation. Here this Review covers the transformative impact of CRISPR-based tools in vertebrate models, highlighting their utility in functional genomics research and disease modeling.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revolution of Biotechnology with CRISPR.","authors":"Kyungjae Myung","doi":"10.1038/s12276-025-01452-x","DOIUrl":"https://doi.org/10.1038/s12276-025-01452-x","url":null,"abstract":"","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revolutionizing CRISPR technology with artificial intelligence.","authors":"Min-Gyeong Kim, Min-Ji Go, Seung-Hun Kang, Soo-Hwan Jeong, Kayeong Lim","doi":"10.1038/s12276-025-01462-9","DOIUrl":"https://doi.org/10.1038/s12276-025-01462-9","url":null,"abstract":"<p><p>Genome engineering has made remarkable strides, evolving from DNA-binding proteins such as zinc fingers and transcription activator-like effectors to CRISPR-Cas systems. CRISPR technology has revolutionized the field through its simplicity and ability to target specific genome regions via guide RNA and Cas proteins. Progress in CRISPR tools-CRISPR nucleases, base editors and prime editors-has expanded the toolkit to induce targeted insertions or deletions, nucleotide conversions and a wider array of genetic alterations. Nevertheless, variations in editing outcomes across cell types and unintended off-target effects still present substantial hurdles. Artificial intelligence (AI), which has seen rapid advances, provides high-level solutions to these problems. By leveraging large datasets from diverse experiments, AI enhances guide RNA design, predicts off-target activities and improves editing efficiency. In addition, AI aids in discovering and designing novel CRISPR systems beyond natural limitations. These developments provide new modalities essential for the innovation of personalized therapies and help to ensure efficiency, precision and safety. Here we discuss the transformative role of AI in advancing CRISPR technology. We highlight how AI contributes to refining nuclease-based editing, base editing and prime editing. Integrating AI with CRISPR technology enhances existing tools and opens doors to next-generation medicine for gene therapy.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging trends in prime editing for precision genome editing.","authors":"Jaesuk Lee, Jiyeon Kweon, Yongsub Kim","doi":"10.1038/s12276-025-01463-8","DOIUrl":"https://doi.org/10.1038/s12276-025-01463-8","url":null,"abstract":"<p><p>Prime editing is an advanced genome editing technology that enables precise genetic modifications without inducing double-strand breaks or requiring donor DNA templates. Prime editing has rapidly become a versatile tool, supporting a wide range of genetic modifications, including point mutations, insertions and deletions. Here we examine the evolution of prime editing technologies, detailing advancements from the initial prime editing systems to recent innovations that enhance editing efficiency. Through structural modifications and improved delivery methods, prime editing has expanded its applicability across eukaryotic systems. By enabling access to previously challenging mutations, prime editing opens new avenues for therapeutic development and precision genetic research, with efficiency, specificity and accessibility expected to shape its future impact in genome engineering.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}