Pub Date : 2025-11-15DOI: 10.1038/s12276-025-01572-4
Yilin Lu, Francesca Storici, Youngkyu Jeon
RNA molecules are now recognized as active regulators of DNA double-strand break repair. In end-joining pathways, nascent transcripts promote repair through RNA:DNA hybrids, end bridging and RNA-templated synthesis. In homologous recombination, RNA:DNA hybrids modulate DNA end resection, recruit repair factors and enable RNA-templated repair, with DNA polymerase ζ emerging as a key reverse transcriptase in this process. Transcription at double-strand break sites generates regulatory RNAs that further influence pathway choice and repair fidelity. Long noncoding RNAs, RNA-binding proteins and RNA modifications add additional control layers. Advances in genomic mapping, reporter assays and in vitro methods are now dissecting these complex RNA-mediated processes, although important challenges remain in capturing their full kinetics and contributions. Finally, RNA-templated genome editing platforms, such as prime editing, harness these principles for precise, programmable DNA repair. Together, these findings position RNA as a multifunctional player in genome maintenance and engineering. RNA, once thought to only carry genetic information, also helps fix dangerous DNA double-strand breaks. It can hold broken DNA ends together, pair with DNA or even act as a template for repair. Research shows RNA directly or indirectly supports multiple repair pathways, helping maintain genome stability. These insights are also driving new genome-editing tools, such as prime editing, that harness RNA’s repair abilities. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"The multiple layers of RNA response in double-strand break repair","authors":"Yilin Lu, Francesca Storici, Youngkyu Jeon","doi":"10.1038/s12276-025-01572-4","DOIUrl":"10.1038/s12276-025-01572-4","url":null,"abstract":"RNA molecules are now recognized as active regulators of DNA double-strand break repair. In end-joining pathways, nascent transcripts promote repair through RNA:DNA hybrids, end bridging and RNA-templated synthesis. In homologous recombination, RNA:DNA hybrids modulate DNA end resection, recruit repair factors and enable RNA-templated repair, with DNA polymerase ζ emerging as a key reverse transcriptase in this process. Transcription at double-strand break sites generates regulatory RNAs that further influence pathway choice and repair fidelity. Long noncoding RNAs, RNA-binding proteins and RNA modifications add additional control layers. Advances in genomic mapping, reporter assays and in vitro methods are now dissecting these complex RNA-mediated processes, although important challenges remain in capturing their full kinetics and contributions. Finally, RNA-templated genome editing platforms, such as prime editing, harness these principles for precise, programmable DNA repair. Together, these findings position RNA as a multifunctional player in genome maintenance and engineering. RNA, once thought to only carry genetic information, also helps fix dangerous DNA double-strand breaks. It can hold broken DNA ends together, pair with DNA or even act as a template for repair. Research shows RNA directly or indirectly supports multiple repair pathways, helping maintain genome stability. These insights are also driving new genome-editing tools, such as prime editing, that harness RNA’s repair abilities. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 11","pages":"2429-2439"},"PeriodicalIF":12.9,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01572-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145551764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-15DOI: 10.1038/s12276-025-01583-1
Islambek Ashyrmamatov, Su Ji Gwak, Su-Young Jin, Ikhyeong Jun, Umit V Ucak, Jay-Yoon Lee, Juyong Lee
Artificial intelligence (AI) is reshaping biomedical research by providing scalable computational frameworks suited to the complexity of biological systems. Central to this revolution are bio/chemical language models, including large language models, which are reconceptualizing molecular structures as a form of 'language' amenable to advanced computational techniques. Here we critically examine the role of these models in biology and chemistry, tracing their evolution from molecular representation to molecular generation and optimization. This review covers key molecular representation strategies for both biological macromolecules and small organic compounds-ranging from protein and nucleotide sequences to single-cell data, string-based chemical formats, graph-based encodings and three-dimensional point clouds-highlighting their respective advantages and inherent limitations in AI applications. The discussion further explores core model architectures, such as bidirectional encoder representations from transformers-like encoders, generative pretrained transformer-like decoders and encoder-decoder transformers, alongside their sophisticated pretraining strategies such as self-supervised learning, multitask learning and retrieval-augmented generation. Key biomedical applications, spanning protein structure and function prediction, de novo protein design, genomic analysis, molecular property prediction, de novo molecular design, reaction prediction and retrosynthesis, are explored through representative studies and emerging trends. Finally, the review considers the emerging landscape of agentic and interactive AI systems, showcasing briefly their potential to automate and accelerate scientific discovery while addressing critical technical, ethical and regulatory considerations that will shape the future trajectory of AI in biomedicine.
{"title":"A survey on large language models in biology and chemistry.","authors":"Islambek Ashyrmamatov, Su Ji Gwak, Su-Young Jin, Ikhyeong Jun, Umit V Ucak, Jay-Yoon Lee, Juyong Lee","doi":"10.1038/s12276-025-01583-1","DOIUrl":"https://doi.org/10.1038/s12276-025-01583-1","url":null,"abstract":"<p><p>Artificial intelligence (AI) is reshaping biomedical research by providing scalable computational frameworks suited to the complexity of biological systems. Central to this revolution are bio/chemical language models, including large language models, which are reconceptualizing molecular structures as a form of 'language' amenable to advanced computational techniques. Here we critically examine the role of these models in biology and chemistry, tracing their evolution from molecular representation to molecular generation and optimization. This review covers key molecular representation strategies for both biological macromolecules and small organic compounds-ranging from protein and nucleotide sequences to single-cell data, string-based chemical formats, graph-based encodings and three-dimensional point clouds-highlighting their respective advantages and inherent limitations in AI applications. The discussion further explores core model architectures, such as bidirectional encoder representations from transformers-like encoders, generative pretrained transformer-like decoders and encoder-decoder transformers, alongside their sophisticated pretraining strategies such as self-supervised learning, multitask learning and retrieval-augmented generation. Key biomedical applications, spanning protein structure and function prediction, de novo protein design, genomic analysis, molecular property prediction, de novo molecular design, reaction prediction and retrosynthesis, are explored through representative studies and emerging trends. Finally, the review considers the emerging landscape of agentic and interactive AI systems, showcasing briefly their potential to automate and accelerate scientific discovery while addressing critical technical, ethical and regulatory considerations that will shape the future trajectory of AI in biomedicine.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145551721","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}
Pub Date : 2025-11-14DOI: 10.1038/s12276-025-01575-1
Nathanael B. Kegel, Nurseda Yilmaz Demirel, Timo Glatter, Katharina Höfer, Andreas Kaufmann, Stefan Bauer
Recent discoveries suggesting that RNA can be modified with sialylated glycans (termed glycoRNA) could broaden our understanding of cellular glycosylation beyond traditional proteins and lipids. However, the pathway of RNA-glycosylation and its biological function remain elusive. Following the original glycoRNA isolation protocol, we also detect labeled glycans in small RNA preparations. However, glycosylated molecules showed resistance to treatment with RNase A/T1 but were sensitive to proteinase K digestion under denaturing conditions. Using liquid chromatography-mass spectrometry-based proteomics we here detect various proteins that copurify with small but not large RNA preparations isolated from human or murine cells, including the glycosylated membrane protein LAMP1. Importantly, we further demonstrate that recombinant soluble LAMP1 can be purified following the glycoRNA isolation method. These findings suggest that glycoproteins copurify with RNA using current glycoRNA purification protocols, thus representing a considerable source of glycans in samples of glycoRNA. Glycosylation, a process where sugars attach to molecules, is known to modify proteins and lipids. Recently, researchers discovered that RNA can also be glycosylated. This study explores the presence of glycoproteins in RNA samples, which might affect the study of glycoRNA. Researchers used a method involving metabolic labeling and silica columns to study glycoRNA. They found that glycoproteins, such as LAMP1, copurify with RNA, meaning that they are extracted together during the purification process. This copurification is influenced by the presence of intact RNA and alcohol concentration. The study concludes that glycoproteins can mimic glycoRNA owing to their similar properties, potentially complicating research. Future studies should refine methods to separate these molecules more effectively, ensuring the accurate analysis of glycoRNA. This could improve our understanding of RNA modifications and their roles in health and disease. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Proteins are a source of glycans found in preparations of glycoRNA","authors":"Nathanael B. Kegel, Nurseda Yilmaz Demirel, Timo Glatter, Katharina Höfer, Andreas Kaufmann, Stefan Bauer","doi":"10.1038/s12276-025-01575-1","DOIUrl":"10.1038/s12276-025-01575-1","url":null,"abstract":"Recent discoveries suggesting that RNA can be modified with sialylated glycans (termed glycoRNA) could broaden our understanding of cellular glycosylation beyond traditional proteins and lipids. However, the pathway of RNA-glycosylation and its biological function remain elusive. Following the original glycoRNA isolation protocol, we also detect labeled glycans in small RNA preparations. However, glycosylated molecules showed resistance to treatment with RNase A/T1 but were sensitive to proteinase K digestion under denaturing conditions. Using liquid chromatography-mass spectrometry-based proteomics we here detect various proteins that copurify with small but not large RNA preparations isolated from human or murine cells, including the glycosylated membrane protein LAMP1. Importantly, we further demonstrate that recombinant soluble LAMP1 can be purified following the glycoRNA isolation method. These findings suggest that glycoproteins copurify with RNA using current glycoRNA purification protocols, thus representing a considerable source of glycans in samples of glycoRNA. Glycosylation, a process where sugars attach to molecules, is known to modify proteins and lipids. Recently, researchers discovered that RNA can also be glycosylated. This study explores the presence of glycoproteins in RNA samples, which might affect the study of glycoRNA. Researchers used a method involving metabolic labeling and silica columns to study glycoRNA. They found that glycoproteins, such as LAMP1, copurify with RNA, meaning that they are extracted together during the purification process. This copurification is influenced by the presence of intact RNA and alcohol concentration. The study concludes that glycoproteins can mimic glycoRNA owing to their similar properties, potentially complicating research. Future studies should refine methods to separate these molecules more effectively, ensuring the accurate analysis of glycoRNA. This could improve our understanding of RNA modifications and their roles in health and disease. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 11","pages":"2505-2516"},"PeriodicalIF":12.9,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01575-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145514829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from colorectal cancer (CRLM) remain poorly understood. Here we show that patients with CRLM whose liver metastases (LM) exhibited tumor fibrosis (Fibrosis+ LM) had significantly worse progression-free survival (P = 0.025) and overall survival (P = 0.008). Single-cell RNA sequencing revealed that the tumor microenvironment of the Fibrosis+ LM was characterized by T cells with an exhausted phenotype, macrophages displaying a profibrotic and suppressive phenotype and fibrosis-promoting fibroblasts. Further investigation highlighted the pivotal role of VCAN_eCAF in remodeling the tumor fibrosis in the tumor microenvironment of Fibrosis+ LM, emphasizing potential targetable interactions such as FGF23 or FGF3-FGFR1. Validation through multiplex immunohistochemistry/immunofluorescence and spatial transcriptomics supported these findings. Here we present a comprehensive single-cell atlas of tumor fibrosis in LM, revealing the intricate multicellular environment and molecular features associated with it. These insights deepen our understanding of tumor fibrosis mechanisms and inform improved clinical diagnosis and treatment strategies. The liver is a common site for cancer spread, especially from colorectal cancer. This study looks at how fibrosis in liver metastases affects treatment and survival. Researchers studied 471 patients with liver metastases from colorectal cancer. They examined tissue samples to see how fibrosis impacts survival and used advanced techniques such as single-cell RNA sequencing to understand the tumor environment better. They found that patients with more fibrosis had worse survival rates. The study also revealed that fibrosis changes the tumor environment, making it harder for the immune system to fight cancer. This includes an increase in certain immune cells that suppress the body’s defense against tumors. The researchers suggest that targeting fibrosis could improve treatment outcomes. In the future, therapies that reduce fibrosis might help enhance the effectiveness of cancer treatments and improve patient survival. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Single-cell transcriptomic profiling reveals liver fibrosis in colorectal cancer liver metastasis","authors":"Yiqiao Deng, Chengyao Guo, Xiaomeng Liu, Xin Li, Jianmei Liu, Wenjie Liu, Jinghua Chen, Zhen Huang, Yefan Zhang, Xinyu Bi, Jianjun Zhao, Jianguo Zhou, Zhiyu Li, Hongliang Wu, Baocai Xing, Qichen Chen, Hong Zhao","doi":"10.1038/s12276-025-01573-3","DOIUrl":"10.1038/s12276-025-01573-3","url":null,"abstract":"Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from colorectal cancer (CRLM) remain poorly understood. Here we show that patients with CRLM whose liver metastases (LM) exhibited tumor fibrosis (Fibrosis+ LM) had significantly worse progression-free survival (P = 0.025) and overall survival (P = 0.008). Single-cell RNA sequencing revealed that the tumor microenvironment of the Fibrosis+ LM was characterized by T cells with an exhausted phenotype, macrophages displaying a profibrotic and suppressive phenotype and fibrosis-promoting fibroblasts. Further investigation highlighted the pivotal role of VCAN_eCAF in remodeling the tumor fibrosis in the tumor microenvironment of Fibrosis+ LM, emphasizing potential targetable interactions such as FGF23 or FGF3-FGFR1. Validation through multiplex immunohistochemistry/immunofluorescence and spatial transcriptomics supported these findings. Here we present a comprehensive single-cell atlas of tumor fibrosis in LM, revealing the intricate multicellular environment and molecular features associated with it. These insights deepen our understanding of tumor fibrosis mechanisms and inform improved clinical diagnosis and treatment strategies. The liver is a common site for cancer spread, especially from colorectal cancer. This study looks at how fibrosis in liver metastases affects treatment and survival. Researchers studied 471 patients with liver metastases from colorectal cancer. They examined tissue samples to see how fibrosis impacts survival and used advanced techniques such as single-cell RNA sequencing to understand the tumor environment better. They found that patients with more fibrosis had worse survival rates. The study also revealed that fibrosis changes the tumor environment, making it harder for the immune system to fight cancer. This includes an increase in certain immune cells that suppress the body’s defense against tumors. The researchers suggest that targeting fibrosis could improve treatment outcomes. In the future, therapies that reduce fibrosis might help enhance the effectiveness of cancer treatments and improve patient survival. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 11","pages":"2517-2532"},"PeriodicalIF":12.9,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01573-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145551830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-14DOI: 10.1038/s12276-025-01587-x
Shuang Lu, Xingyu Wei, Huan Zhu, Leyuan Li, Wenqian Zhang, Pei Du, Yaqin Yu, Meiling Zheng, Zhi Hu, Sujie Jia, Qianjin Lu, Ming Zhao
B cell malfunction is implicated in the pathogenesis of systemic lupus erythematosus (SLE) through the release of proinflammatory cytokines and the production of autoreactive antibodies. RNA N6-methyladenosine (m6A) is the predominant post-transcriptional RNA modification that has been reported to control various biological processes. Whether RNA m6A alteration and m6A reader protein YTHDF1 contribute to B cell activation and terminal B cell differentiation in SLE has not been fully demonstrated. Here we observed that SLE peripheral B cell subsets, activated B cells and differentiated plasma cells (PCs) had abnormally elevated levels of YTHDF1, the deficit of which attenuated PC differentiation both in vitro and in mouse models that have been immunized with keyhole limpet hemocyanin (KLH) or N-propionyl polysialic acid (NP–KLH). Utilizing RNA sequencing, RNA immunoprecipitation, m6A immunoprecipitation and other functional experiments, we have identified and described a PC-promoting role of YTHDF1. YTHDF1 binds to the m6A-marked 3′ untranslated region of transcription factor IRF4 messenger RNA to enhance its stability, thereby facilitating PC differentiation. Depletion of YTHDF1 hindered the differentiation of PCs, reduced the generation of autoantibodies and ameliorated the lupus-like phenotypes in an imiquimod-treated mouse model. Overall, this study highlights a distinct role of YTHDF1 in promoting PC differentiation through the direct regulation of IRF4 in an m6A-dependent manner and identifies YTHDF1 as a potential target for the treatment of SLE. Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which the immune system attacks the body’s own tissues. Researchers have been exploring ways to manage SLE by targeting specific immune cells called B cells. This study investigates a protein called YTHDF1, which is involved in the regulation of B cells. They found that YTHDF1 levels are higher in certain B cells of patients with SLE. They conducted experiments using both human cells and mice to understand how YTHDF1 affects B cell behavior. They used techniques such as gene editing and RNA analysis to study the effects of removing YTHDF1 from B cells. This study showed that without YTHDF1, B cells had trouble developing into plasma cells, which are crucial for producing antibodies. The results suggest that YTHDF1 helps to stabilize a key molecule called IRF4, which is important for plasma cell development. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"RNA N6-methyladenosine reader protein YTHDF1 promotes plasma cell differentiation via IRF4 regulation in systemic lupus erythematosus","authors":"Shuang Lu, Xingyu Wei, Huan Zhu, Leyuan Li, Wenqian Zhang, Pei Du, Yaqin Yu, Meiling Zheng, Zhi Hu, Sujie Jia, Qianjin Lu, Ming Zhao","doi":"10.1038/s12276-025-01587-x","DOIUrl":"10.1038/s12276-025-01587-x","url":null,"abstract":"B cell malfunction is implicated in the pathogenesis of systemic lupus erythematosus (SLE) through the release of proinflammatory cytokines and the production of autoreactive antibodies. RNA N6-methyladenosine (m6A) is the predominant post-transcriptional RNA modification that has been reported to control various biological processes. Whether RNA m6A alteration and m6A reader protein YTHDF1 contribute to B cell activation and terminal B cell differentiation in SLE has not been fully demonstrated. Here we observed that SLE peripheral B cell subsets, activated B cells and differentiated plasma cells (PCs) had abnormally elevated levels of YTHDF1, the deficit of which attenuated PC differentiation both in vitro and in mouse models that have been immunized with keyhole limpet hemocyanin (KLH) or N-propionyl polysialic acid (NP–KLH). Utilizing RNA sequencing, RNA immunoprecipitation, m6A immunoprecipitation and other functional experiments, we have identified and described a PC-promoting role of YTHDF1. YTHDF1 binds to the m6A-marked 3′ untranslated region of transcription factor IRF4 messenger RNA to enhance its stability, thereby facilitating PC differentiation. Depletion of YTHDF1 hindered the differentiation of PCs, reduced the generation of autoantibodies and ameliorated the lupus-like phenotypes in an imiquimod-treated mouse model. Overall, this study highlights a distinct role of YTHDF1 in promoting PC differentiation through the direct regulation of IRF4 in an m6A-dependent manner and identifies YTHDF1 as a potential target for the treatment of SLE. Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which the immune system attacks the body’s own tissues. Researchers have been exploring ways to manage SLE by targeting specific immune cells called B cells. This study investigates a protein called YTHDF1, which is involved in the regulation of B cells. They found that YTHDF1 levels are higher in certain B cells of patients with SLE. They conducted experiments using both human cells and mice to understand how YTHDF1 affects B cell behavior. They used techniques such as gene editing and RNA analysis to study the effects of removing YTHDF1 from B cells. This study showed that without YTHDF1, B cells had trouble developing into plasma cells, which are crucial for producing antibodies. The results suggest that YTHDF1 helps to stabilize a key molecule called IRF4, which is important for plasma cell development. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 11","pages":"2574-2587"},"PeriodicalIF":12.9,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01587-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145551803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1038/s12276-025-01584-0
Jeong Hoon Pan, Nukhet Aykin-Burns, Kimberly J. Krager, Hyo Ri Shin, Chae Hwan Lee, Jin Hyup Lee, Byungwhi Kong, JaeEun Myoung, Kyung-Chul Choi, Jae Kyeom Kim
Recent epidemiological studies have shown that dietary fructose intake is associated with an increased risk of colorectal cancer, yet its specific molecular mechanisms in colon carcinogenesis remain underexplored. Here we investigate the molecular mechanisms by which dietary fructose contributes to colon carcinogenesis, focusing on the role of mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2). Using an unbiased multiomics approach (transcriptomics and proteomics), liver and colon tissues from fructose-fed wild-type mice were analyzed to identify key genes involved in cancer-related pathways. In addition, human liver transcriptomic data (GSE256398) were analyzed to confirm alterations in aryl hydrocarbon receptor (AhR) signaling and the sirtuin (SIRT)3–IDH2 axis. IDH2-knockout mice were exposed to a dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), to validate IDH2’s role in colon cancer development. In vitro, fructose’s effects on SIRT3 expression and IDH2 activity were assessed. Fructose-fed wild-type mice exhibited suppressed AhR signaling, increased oxidative stress and mitochondrial dysfunction via the SIRT3–IDH2 axis. In human liver datasets, AhR-associated genes and SIRT3–IDH2 expression were reduced in metabolic dysfunction-associated steatotic liver disease and cirrhosis. The IDH2-knockout mice showed heightened DNA damage, colonic tumorigenesis and mitochondrial and glutathione-mediated detoxification disruptions following PhIP exposure. In vitro, fructose reduced SIRT3 expression and IDH2 activity, further supporting its role in promoting colon carcinogenesis. Fructose promotes colon carcinogenesis by disrupting mitochondrial function and impairing DNA damage response mechanisms, particularly through SIRT3–IDH2 axis suppression. These findings highlight the critical role of mitochondrial dysfunction in fructose-induced carcinogenesis and suggest the SIRT3–IDH2 axis as a potential therapeutic target. Fructose is a common sweetener, but its health effects are debated. Several studies suggest it may increase the risk of colon cancer. This study explores how fructose might contribute to cancer development. Researchers used mice to study the effects of fructose on liver and colon tissues. They focused on a gene called IDH2, which is involved in energy production and glutathione synthesis. The study found that fructose can disrupt the function of IDH2, leading to increased oxidative stress and impaired carcinogen detoxification processes. This disruption may make cells more vulnerable to DNA damage and cancer. The researchers concluded that fructose could play a role in colon cancer development by affecting mitochondrial function and detoxification pathways. Future research could explore ways to mitigate these effects, potentially offering new strategies for cancer prevention related to diet. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"SIRT3–IDH2 axis is a target of dietary fructose: implication of IDH2 as a key player in dietary carcinogen toxicity in mice colon","authors":"Jeong Hoon Pan, Nukhet Aykin-Burns, Kimberly J. Krager, Hyo Ri Shin, Chae Hwan Lee, Jin Hyup Lee, Byungwhi Kong, JaeEun Myoung, Kyung-Chul Choi, Jae Kyeom Kim","doi":"10.1038/s12276-025-01584-0","DOIUrl":"10.1038/s12276-025-01584-0","url":null,"abstract":"Recent epidemiological studies have shown that dietary fructose intake is associated with an increased risk of colorectal cancer, yet its specific molecular mechanisms in colon carcinogenesis remain underexplored. Here we investigate the molecular mechanisms by which dietary fructose contributes to colon carcinogenesis, focusing on the role of mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2). Using an unbiased multiomics approach (transcriptomics and proteomics), liver and colon tissues from fructose-fed wild-type mice were analyzed to identify key genes involved in cancer-related pathways. In addition, human liver transcriptomic data (GSE256398) were analyzed to confirm alterations in aryl hydrocarbon receptor (AhR) signaling and the sirtuin (SIRT)3–IDH2 axis. IDH2-knockout mice were exposed to a dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), to validate IDH2’s role in colon cancer development. In vitro, fructose’s effects on SIRT3 expression and IDH2 activity were assessed. Fructose-fed wild-type mice exhibited suppressed AhR signaling, increased oxidative stress and mitochondrial dysfunction via the SIRT3–IDH2 axis. In human liver datasets, AhR-associated genes and SIRT3–IDH2 expression were reduced in metabolic dysfunction-associated steatotic liver disease and cirrhosis. The IDH2-knockout mice showed heightened DNA damage, colonic tumorigenesis and mitochondrial and glutathione-mediated detoxification disruptions following PhIP exposure. In vitro, fructose reduced SIRT3 expression and IDH2 activity, further supporting its role in promoting colon carcinogenesis. Fructose promotes colon carcinogenesis by disrupting mitochondrial function and impairing DNA damage response mechanisms, particularly through SIRT3–IDH2 axis suppression. These findings highlight the critical role of mitochondrial dysfunction in fructose-induced carcinogenesis and suggest the SIRT3–IDH2 axis as a potential therapeutic target. Fructose is a common sweetener, but its health effects are debated. Several studies suggest it may increase the risk of colon cancer. This study explores how fructose might contribute to cancer development. Researchers used mice to study the effects of fructose on liver and colon tissues. They focused on a gene called IDH2, which is involved in energy production and glutathione synthesis. The study found that fructose can disrupt the function of IDH2, leading to increased oxidative stress and impaired carcinogen detoxification processes. This disruption may make cells more vulnerable to DNA damage and cancer. The researchers concluded that fructose could play a role in colon cancer development by affecting mitochondrial function and detoxification pathways. Future research could explore ways to mitigate these effects, potentially offering new strategies for cancer prevention related to diet. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 11","pages":"2643-2656"},"PeriodicalIF":12.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01584-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145551788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1038/s12276-025-01574-2
Qihang Su, Heng’an Ge, Jun Li, Centao Liu, Liyang Chen, Jie Li, Qiuchen Cai, Chenglong Huang, Xiaofei Feng, Dandan Li, Biao Cheng
Although angiogenesis following tendon injury was expected to provide nutrients for regeneration and repair, excessive angiogenesis may be associated with poor long-term outcomes in tendinopathy. Here we aim to explore the pathological role of angiogenesis in the progression of tendinopathy. Patients with tendinopathy were categorized into a hypervascularization group (HyperV) and a hypovascularization group (HypoV), and postarthroscopic outcome and histopathology were compared. In addiiton, tendon injury models and tenocyte stress models were employed to investigate the temporal–spatial vascular pattern characteristics and mechanisms involved in the progression of tendinopathy. This study finds that the HyperV group exhibited worse postoperative pain and functional outcomes and higher Bonar’s pathological scores and vascular density. Bulk RNA sequencing and pathological staining revealed that decreased FHL2 and increased YAP1/sFRP2 expression in tenocytes were strongly associated with disorganized tissue pathology, aggravated inflammation and increased vascular abundance in the HyperV group and tendon injury models (Td-Inj and Td-Sut groups). Three-dimensional vascular imaging demonstrated the formation of morphologically complex and abnormally distributed blood vessels in the Td-Inj and Td-Sut groups, which was significantly alleviated by YAP1 knockdown. In activated tenocytes, FHL2 deficiency-mediated YAP1 overexpression led to the overexpression and extracellular secretion of sFRP2, thereby enhancing endothelial angiogenesis. FHL2 overexpression partly mitigated vascular remodeling and improved tendon blood perfusion in rats. In summary, FHL2/YAP1/sFRP2-mediated pathological vascular remodeling disrupts the homeostasis of tendon repair and regeneration. This study underscores the importance of a systematic vascular assessment, incorporating abundance, morphology, and spatial distribution, in tendinopathy. Tendinopathy is a condition where tendons become damaged, causing pain and dysfunction. This study explores how blood vessel growth, or angiogenesis, affects tendinopathy. Researchers found that excessive blood vessel growth in tendons can worsen the condition rather than help it heal. The study involved patients with chronic rotator cuff tendinopathy and used rat models to simulate tendon injuries. Researchers focused on three proteins: FHL2, YAP1 and sFRP2. They discovered that low levels of FHL2 and high levels of YAP1 and sFRP2 are linked to abnormal blood vessel growth and poor tendon healing. By increasing FHL2 levels in injured tendons, they improved tissue structure and blood flow, suggesting a potential treatment strategy. The study concludes that managing blood vessel growth in tendons could lead to better treatments for tendinopathy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Temporal vascular pattern remodeling mediated by the FHL2/sFRP2 signaling pathway in tenocytes affects tendon repair and regeneration","authors":"Qihang Su, Heng’an Ge, Jun Li, Centao Liu, Liyang Chen, Jie Li, Qiuchen Cai, Chenglong Huang, Xiaofei Feng, Dandan Li, Biao Cheng","doi":"10.1038/s12276-025-01574-2","DOIUrl":"10.1038/s12276-025-01574-2","url":null,"abstract":"Although angiogenesis following tendon injury was expected to provide nutrients for regeneration and repair, excessive angiogenesis may be associated with poor long-term outcomes in tendinopathy. Here we aim to explore the pathological role of angiogenesis in the progression of tendinopathy. Patients with tendinopathy were categorized into a hypervascularization group (HyperV) and a hypovascularization group (HypoV), and postarthroscopic outcome and histopathology were compared. In addiiton, tendon injury models and tenocyte stress models were employed to investigate the temporal–spatial vascular pattern characteristics and mechanisms involved in the progression of tendinopathy. This study finds that the HyperV group exhibited worse postoperative pain and functional outcomes and higher Bonar’s pathological scores and vascular density. Bulk RNA sequencing and pathological staining revealed that decreased FHL2 and increased YAP1/sFRP2 expression in tenocytes were strongly associated with disorganized tissue pathology, aggravated inflammation and increased vascular abundance in the HyperV group and tendon injury models (Td-Inj and Td-Sut groups). Three-dimensional vascular imaging demonstrated the formation of morphologically complex and abnormally distributed blood vessels in the Td-Inj and Td-Sut groups, which was significantly alleviated by YAP1 knockdown. In activated tenocytes, FHL2 deficiency-mediated YAP1 overexpression led to the overexpression and extracellular secretion of sFRP2, thereby enhancing endothelial angiogenesis. FHL2 overexpression partly mitigated vascular remodeling and improved tendon blood perfusion in rats. In summary, FHL2/YAP1/sFRP2-mediated pathological vascular remodeling disrupts the homeostasis of tendon repair and regeneration. This study underscores the importance of a systematic vascular assessment, incorporating abundance, morphology, and spatial distribution, in tendinopathy. Tendinopathy is a condition where tendons become damaged, causing pain and dysfunction. This study explores how blood vessel growth, or angiogenesis, affects tendinopathy. Researchers found that excessive blood vessel growth in tendons can worsen the condition rather than help it heal. The study involved patients with chronic rotator cuff tendinopathy and used rat models to simulate tendon injuries. Researchers focused on three proteins: FHL2, YAP1 and sFRP2. They discovered that low levels of FHL2 and high levels of YAP1 and sFRP2 are linked to abnormal blood vessel growth and poor tendon healing. By increasing FHL2 levels in injured tendons, they improved tissue structure and blood flow, suggesting a potential treatment strategy. The study concludes that managing blood vessel growth in tendons could lead to better treatments for tendinopathy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 11","pages":"2533-2558"},"PeriodicalIF":12.9,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01574-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145551833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1038/s12276-025-01580-4
Yushan Liu, Katherine M. Murphy, Yu Fan Hung, Taejoon Won
Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organs simultaneously, complicating diagnosis and treatment. Despite extensive research, tissue-specific autoantigens and precise disease mechanisms remain unclear. Hallmark SLE autoantibodies primarily target nuclear antigens ubiquitously expressed across all tissues, limiting their diagnostic and therapeutic specificity. Myocarditis is a severe cardiovascular complication of SLE with a high mortality. However, not all patients with lupus myocarditis test positive for hallmark SLE antibodies, and their titers show no significant differences between patients with SLE with and without myocarditis, suggesting the involvement of additional, unidentified mechanisms. Autoimmunity against cardiac myosin heavy chain (MyHC) is a well-established driver of various forms of autoimmune myocarditis. However, the role of autoreactive T cells and autoantibodies targeting MyHC or other cardiac antigens in lupus myocarditis remains largely unknown. Here, in this Review, we offer an overview of the current knowledge on autoreactive T cells and autoantibodies identified in primary SLE or autoimmune myocarditis conditions from both clinical and preclinical studies. We also propose a novel two-stage model for lupus myocarditis pathogenesis, integrating both nuclear and cardiac antigen targets. Finally, we discuss antigen-specific regulatory T cells and chimeric antigen receptor T cells as promising therapeutic strategies for future research and clinical applications. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs, including the heart. Lupus myocarditis, a severe heart inflammation, is a major complication of SLE. Researchers aim to understand the mechanisms behind lupus myocarditis. The authors explore how the immune system, particularly autoantibodies and autoreactive T cells, contributes to heart damage in SLE. They discuss how these immune components target both nuclear antigens and heart-specific proteins such as cardiac myosin heavy chain. The study highlights the role of tissue-resident memory T cells, which stay in the heart and may trigger inflammation during lupus flare-ups. The previous findings suggest that targeting specific immune pathways could lead to better treatments for lupus myocarditis. Future research may focus on developing therapies that regulate these immune responses, potentially improving outcomes for patients with SLE-related heart issues. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Pathogenic drivers of lupus myocarditis and potential therapeutic targets","authors":"Yushan Liu, Katherine M. Murphy, Yu Fan Hung, Taejoon Won","doi":"10.1038/s12276-025-01580-4","DOIUrl":"10.1038/s12276-025-01580-4","url":null,"abstract":"Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organs simultaneously, complicating diagnosis and treatment. Despite extensive research, tissue-specific autoantigens and precise disease mechanisms remain unclear. Hallmark SLE autoantibodies primarily target nuclear antigens ubiquitously expressed across all tissues, limiting their diagnostic and therapeutic specificity. Myocarditis is a severe cardiovascular complication of SLE with a high mortality. However, not all patients with lupus myocarditis test positive for hallmark SLE antibodies, and their titers show no significant differences between patients with SLE with and without myocarditis, suggesting the involvement of additional, unidentified mechanisms. Autoimmunity against cardiac myosin heavy chain (MyHC) is a well-established driver of various forms of autoimmune myocarditis. However, the role of autoreactive T cells and autoantibodies targeting MyHC or other cardiac antigens in lupus myocarditis remains largely unknown. Here, in this Review, we offer an overview of the current knowledge on autoreactive T cells and autoantibodies identified in primary SLE or autoimmune myocarditis conditions from both clinical and preclinical studies. We also propose a novel two-stage model for lupus myocarditis pathogenesis, integrating both nuclear and cardiac antigen targets. Finally, we discuss antigen-specific regulatory T cells and chimeric antigen receptor T cells as promising therapeutic strategies for future research and clinical applications. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs, including the heart. Lupus myocarditis, a severe heart inflammation, is a major complication of SLE. Researchers aim to understand the mechanisms behind lupus myocarditis. The authors explore how the immune system, particularly autoantibodies and autoreactive T cells, contributes to heart damage in SLE. They discuss how these immune components target both nuclear antigens and heart-specific proteins such as cardiac myosin heavy chain. The study highlights the role of tissue-resident memory T cells, which stay in the heart and may trigger inflammation during lupus flare-ups. The previous findings suggest that targeting specific immune pathways could lead to better treatments for lupus myocarditis. Future research may focus on developing therapies that regulate these immune responses, potentially improving outcomes for patients with SLE-related heart issues. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 11","pages":"2408-2417"},"PeriodicalIF":12.9,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01580-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1038/s12276-025-01571-5
Yechan Choi, Minkyu Shim, Suhn Hyung Kim, Duk Ki Kim, Juhee Jeong, Jinyoung Byeon, Giyong Jang, Ji-Yeon Kim, Paul Robson, Charles Lee, Han-Byoel Lee, Keehoon Jung
Intratumoral myeloid cells are highly heterogeneous in terms of development and function and are pivotal for forming and regulating the tumor microenvironment. However, the myeloid milieu in triple-negative breast cancer (TNBC) remains poorly understood. Here, to elucidate this myeloid milieu, we integrated in-house and public single-cell RNA sequencing data. We detected diverse neutrophil and mononuclear-phagocyte subtypes and delineated their developmental trajectories and functions. Of particular interest were the VEGFAhi neutrophil and SPP1hi macrophage subtypes, which displayed protumoral functions, including angiogenesis. Spatial transcriptomics revealed that they colocalized with epithelial cancer cells and APLNhi endothelial tip cells in a hypoxic region forming an angiogenic niche. Moreover, patients with SPP1hi macrophage-enriched TNBC showed poor prognosis, which worsened in patients who also displayed abundant VEGFAhi neutrophils. These subtypes were also conserved in multiple murine TNBC models. This comprehensive analysis of the myeloid population in TNBC thus reveals a previously undercharacterized interaction between VEGFAhi neutrophils and SPP1hi macrophages, elucidating their contributions in the formation of an angiogenic niche. Breast cancer is a common cancer and a leading cause of cancer-related deaths. Triple-negative breast cancer (TNBC) is particularly challenging to treat due to the lack of specific targets for therapy. This study explores the role of myeloid cells in TNBC. The researchers used single-cell RNA sequencing to analyze myeloid cells from TNBC samples. They identified various subtypes of these cells, including neutrophils and macrophages, which have different roles in the tumor environment. The study found that certain subtypes, such as SPP1hi macrophages and VEGFAhi neutrophils, colocalize in the tumor microenvironment and participate in promoting blood vessel formation, leading to poor patient outcomes. The findings suggest that targeting these specific myeloid cell subtypes could improve treatment for TNBC. Future research may focus on developing therapies that specifically target these protumoral cells to enhance patient survival. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Single-cell transcriptomics of the myeloid milieu reveals an angiogenic niche in triple-negative breast cancer","authors":"Yechan Choi, Minkyu Shim, Suhn Hyung Kim, Duk Ki Kim, Juhee Jeong, Jinyoung Byeon, Giyong Jang, Ji-Yeon Kim, Paul Robson, Charles Lee, Han-Byoel Lee, Keehoon Jung","doi":"10.1038/s12276-025-01571-5","DOIUrl":"10.1038/s12276-025-01571-5","url":null,"abstract":"Intratumoral myeloid cells are highly heterogeneous in terms of development and function and are pivotal for forming and regulating the tumor microenvironment. However, the myeloid milieu in triple-negative breast cancer (TNBC) remains poorly understood. Here, to elucidate this myeloid milieu, we integrated in-house and public single-cell RNA sequencing data. We detected diverse neutrophil and mononuclear-phagocyte subtypes and delineated their developmental trajectories and functions. Of particular interest were the VEGFAhi neutrophil and SPP1hi macrophage subtypes, which displayed protumoral functions, including angiogenesis. Spatial transcriptomics revealed that they colocalized with epithelial cancer cells and APLNhi endothelial tip cells in a hypoxic region forming an angiogenic niche. Moreover, patients with SPP1hi macrophage-enriched TNBC showed poor prognosis, which worsened in patients who also displayed abundant VEGFAhi neutrophils. These subtypes were also conserved in multiple murine TNBC models. This comprehensive analysis of the myeloid population in TNBC thus reveals a previously undercharacterized interaction between VEGFAhi neutrophils and SPP1hi macrophages, elucidating their contributions in the formation of an angiogenic niche. Breast cancer is a common cancer and a leading cause of cancer-related deaths. Triple-negative breast cancer (TNBC) is particularly challenging to treat due to the lack of specific targets for therapy. This study explores the role of myeloid cells in TNBC. The researchers used single-cell RNA sequencing to analyze myeloid cells from TNBC samples. They identified various subtypes of these cells, including neutrophils and macrophages, which have different roles in the tumor environment. The study found that certain subtypes, such as SPP1hi macrophages and VEGFAhi neutrophils, colocalize in the tumor microenvironment and participate in promoting blood vessel formation, leading to poor patient outcomes. The findings suggest that targeting these specific myeloid cell subtypes could improve treatment for TNBC. Future research may focus on developing therapies that specifically target these protumoral cells to enhance patient survival. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 11","pages":"2487-2504"},"PeriodicalIF":12.9,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01571-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1038/s12276-025-01567-1
Dae-Seok Kim, Jan-Bernd Funcke, Shiuhwei Chen, Kyounghee Min, Toshiharu Onodera, Min Kim, Qian Lin, Chanmin Joung, Joselin Velasco, Megan Virostek, Katarzyna Walendzik, Chitkale Hiremath, Denise K. Marciano, Philipp E. Scherer
Endotrophin (ETP), a cleavage product of the C5 domain of collagen VI α3 (COL6A3), plays a crucial role in extracellular matrix remodeling. Previously established Col6a3-knockout mouse models primarily reflect the consequences of COL6A3 loss rather than the specific effects of ETP depletion, making it challenging to directly assess the functions of ETP. These models either disrupt COL6A3 along with ETP production or express functionally defective COL6A3 while maintaining ETP production. Here we developed and validated a novel ETP-knockout (ETPKO) mouse model that selectively ablates ETP while preserving Col6a3 expression to address these limitations. To generate the ETPKO model, we introduced lox2272 sites and a fluorescent mCherryCAAX reporter into the Col6a3 locus, ensuring that ETP expression is turned off and reporter expression is turned on upon Cre-mediated recombination. Crossing the Col6a3-Etp+mCherryCAAX mouse line with CMV-Cre mice yielded ETPKO mice, in which successful ETP deletion was confirmed by sequencing of genomic DNA and analysis of mCherryCAAX expression. Using this model, we investigated the role of ETP in kidney fibrosis. ETPKO mice subjected to unilateral or bilateral kidney ischemia–reperfusion injury exhibited complete Etp messenger RNA ablation with only a partial reduction in Col6a3 mRNA. Notably, ETP depletion significantly attenuated fibrosis progression, demonstrating a critical contribution of ETP to the pathogenesis of kidney fibrosis. The ETPKO mouse model provides a targeted and specific approach to study ETP function independently of COL6A3 expression. These findings establish ETP as a key driver of fibrosis and position ETPKO mice as a valuable tool for elucidating ETP-mediated mechanisms in preclinical disease models. Collagen type VI is important for tissue structure. It consists of three chains, including COL6A3, which produces a fragment called endotrophin (ETP). Previous mouse models could not isolate the role of ETP without affecting its parent molecule COL6A3. To address this, researchers created a new mouse model that can specifically remove ETP using a technique called CRISPR–Cas9. In this study, researchers used this new model to study kidney fibrosis. They induced kidney injury in mice and found that removing ETP reduced fibrosis and improved kidney function. This suggests ETP plays a key role not only in fibrosis in the kidneys but also in many other tissues. The study used methods such as immunostaining and genetic analysis to confirm these findings. The results show that targeting ETP could be a potential therapeutic approach to fibrotic diseases, which are very difficult to treat. Future research could explore the role of ETP in other conditions and its potential as a therapeutic target. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"ETP-specific-knockout mice reveal endotrophin as a key regulator of kidney fibrosis in ischemia–reperfusion injury models","authors":"Dae-Seok Kim, Jan-Bernd Funcke, Shiuhwei Chen, Kyounghee Min, Toshiharu Onodera, Min Kim, Qian Lin, Chanmin Joung, Joselin Velasco, Megan Virostek, Katarzyna Walendzik, Chitkale Hiremath, Denise K. Marciano, Philipp E. Scherer","doi":"10.1038/s12276-025-01567-1","DOIUrl":"10.1038/s12276-025-01567-1","url":null,"abstract":"Endotrophin (ETP), a cleavage product of the C5 domain of collagen VI α3 (COL6A3), plays a crucial role in extracellular matrix remodeling. Previously established Col6a3-knockout mouse models primarily reflect the consequences of COL6A3 loss rather than the specific effects of ETP depletion, making it challenging to directly assess the functions of ETP. These models either disrupt COL6A3 along with ETP production or express functionally defective COL6A3 while maintaining ETP production. Here we developed and validated a novel ETP-knockout (ETPKO) mouse model that selectively ablates ETP while preserving Col6a3 expression to address these limitations. To generate the ETPKO model, we introduced lox2272 sites and a fluorescent mCherryCAAX reporter into the Col6a3 locus, ensuring that ETP expression is turned off and reporter expression is turned on upon Cre-mediated recombination. Crossing the Col6a3-Etp+mCherryCAAX mouse line with CMV-Cre mice yielded ETPKO mice, in which successful ETP deletion was confirmed by sequencing of genomic DNA and analysis of mCherryCAAX expression. Using this model, we investigated the role of ETP in kidney fibrosis. ETPKO mice subjected to unilateral or bilateral kidney ischemia–reperfusion injury exhibited complete Etp messenger RNA ablation with only a partial reduction in Col6a3 mRNA. Notably, ETP depletion significantly attenuated fibrosis progression, demonstrating a critical contribution of ETP to the pathogenesis of kidney fibrosis. The ETPKO mouse model provides a targeted and specific approach to study ETP function independently of COL6A3 expression. These findings establish ETP as a key driver of fibrosis and position ETPKO mice as a valuable tool for elucidating ETP-mediated mechanisms in preclinical disease models. Collagen type VI is important for tissue structure. It consists of three chains, including COL6A3, which produces a fragment called endotrophin (ETP). Previous mouse models could not isolate the role of ETP without affecting its parent molecule COL6A3. To address this, researchers created a new mouse model that can specifically remove ETP using a technique called CRISPR–Cas9. In this study, researchers used this new model to study kidney fibrosis. They induced kidney injury in mice and found that removing ETP reduced fibrosis and improved kidney function. This suggests ETP plays a key role not only in fibrosis in the kidneys but also in many other tissues. The study used methods such as immunostaining and genetic analysis to confirm these findings. The results show that targeting ETP could be a potential therapeutic approach to fibrotic diseases, which are very difficult to treat. Future research could explore the role of ETP in other conditions and its potential as a therapeutic target. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 11","pages":"2475-2486"},"PeriodicalIF":12.9,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01567-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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