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}
Pub Date : 2025-11-07DOI: 10.1038/s12276-025-01565-3
Jinjoo Lee, Myeong-Ho Kang, Kee-Hyun Kwon, Min-Suk Cha, JungHyub Hong, Yoe-Sik Bae, Seok-Hee Park, Siyoung Yang, Hye Young Kim, Kyung Chul Yoon, Yong-Soo Bae
Understanding the intrahepatic protective immune systems against acetaminophen (APAP)-induced acute liver injury (ALI) is currently limited. Here we reveal that Gram-positive gut-microbiota-derived pathogen-associated molecular patterns promote the CCL2-dependent infiltration of hepatotoxic Ly6Chi monocytes into the APAP-damaged liver, thus inducing APAP-ALI. Conversely, Gram-negative bacterial pathogen-associated molecular patterns activate hepatic CD103⁺ cDC1s to produce IL-15, which in turn expands intrahepatic tissue-resident memory CD8⁺ T (TRM) cells and promotes protective immunity against APAP-derived liver injury. APAP-ALI was further exacerbated in Batf3-knockout and Rag1-knockout mice owing to an increased population of intrahepatic Ly6Chi monocytes in both knockout strains. The adoptive transfer of hepatic CD8+ T cells or hepatic CD103+ cDC1s from wild-type mice ameliorated APAP-ALI in both knockout mice. Notably, CD44+CD69+ TRM cells within hepatic CD8+ T cells, when activated by IL-15/IL-15Rα from hepatic CD103+ cDC1s of APAP mice, played a crucial role in inducing apoptosis of liver-infiltrating monocytes through direct cell-to-cell interactions and granzyme B secretion. Human results supported these animal findings. Our findings underscore the existence of an intrahepatic protective immune system, the hepatic CD103+ cDC1/CD8+ TRM axis, which regulates APAP-ALI by controlling pathogenic monocytes. Acetaminophen is a common pain reliever, but an overdose can cause severe liver damage, known as acute liver injury. Researchers found that gut bacteria influence how immune cells respond to this damage. Signals from Gram-positive bacteria encouraged harmful monocytes to enter the liver and worsen injury, whereas signals from Gram-negative bacteria activated a protective immune pathway. In this pathway, a special liver immune cell type called cDC1s released the molecule IL-15, which stimulated CD8⁺ tissue-resident memory T cells to destroy the harmful monocytes. This CD103⁺ cDC1/IL-15/CD8⁺ tissue-resident memory T cell ‘protective immune axis’ helped limit liver damage in mice, and similar results were supported by human data. The study highlights a promising new therapeutic direction for treating acetaminophen-induced liver injury by strengthening the liver’s own protective immune system. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Discovery of intrahepatic CD103+ cDC1/CD8+ TRM protective immune axis against acetaminophen-induced acute liver injury","authors":"Jinjoo Lee, Myeong-Ho Kang, Kee-Hyun Kwon, Min-Suk Cha, JungHyub Hong, Yoe-Sik Bae, Seok-Hee Park, Siyoung Yang, Hye Young Kim, Kyung Chul Yoon, Yong-Soo Bae","doi":"10.1038/s12276-025-01565-3","DOIUrl":"10.1038/s12276-025-01565-3","url":null,"abstract":"Understanding the intrahepatic protective immune systems against acetaminophen (APAP)-induced acute liver injury (ALI) is currently limited. Here we reveal that Gram-positive gut-microbiota-derived pathogen-associated molecular patterns promote the CCL2-dependent infiltration of hepatotoxic Ly6Chi monocytes into the APAP-damaged liver, thus inducing APAP-ALI. Conversely, Gram-negative bacterial pathogen-associated molecular patterns activate hepatic CD103⁺ cDC1s to produce IL-15, which in turn expands intrahepatic tissue-resident memory CD8⁺ T (TRM) cells and promotes protective immunity against APAP-derived liver injury. APAP-ALI was further exacerbated in Batf3-knockout and Rag1-knockout mice owing to an increased population of intrahepatic Ly6Chi monocytes in both knockout strains. The adoptive transfer of hepatic CD8+ T cells or hepatic CD103+ cDC1s from wild-type mice ameliorated APAP-ALI in both knockout mice. Notably, CD44+CD69+ TRM cells within hepatic CD8+ T cells, when activated by IL-15/IL-15Rα from hepatic CD103+ cDC1s of APAP mice, played a crucial role in inducing apoptosis of liver-infiltrating monocytes through direct cell-to-cell interactions and granzyme B secretion. Human results supported these animal findings. Our findings underscore the existence of an intrahepatic protective immune system, the hepatic CD103+ cDC1/CD8+ TRM axis, which regulates APAP-ALI by controlling pathogenic monocytes. Acetaminophen is a common pain reliever, but an overdose can cause severe liver damage, known as acute liver injury. Researchers found that gut bacteria influence how immune cells respond to this damage. Signals from Gram-positive bacteria encouraged harmful monocytes to enter the liver and worsen injury, whereas signals from Gram-negative bacteria activated a protective immune pathway. In this pathway, a special liver immune cell type called cDC1s released the molecule IL-15, which stimulated CD8⁺ tissue-resident memory T cells to destroy the harmful monocytes. This CD103⁺ cDC1/IL-15/CD8⁺ tissue-resident memory T cell ‘protective immune axis’ helped limit liver damage in mice, and similar results were supported by human data. The study highlights a promising new therapeutic direction for treating acetaminophen-induced liver injury by strengthening the liver’s own protective immune system. 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":"2458-2474"},"PeriodicalIF":12.9,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01565-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472529","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}
A method for analyzing tumor evolution based on bulk RNA-sequencing data has not been reported yet. The epithelial–mesenchymal transition (EMT) is an evolutionarily conserved cellular program with high heterogeneity and plasticity. In this study, we proposed an EMT heterogeneity-based molecular typing (EHBMT) method to visualize cancer evolution and guide personalized medicine. Multiplex immunohistochemical assay and single-cell analysis were performed to confirm the feasibility of this method. EHBMT divided gastric (cancer) tissues into an epithelial phenotype cluster (EPC), hybrid epithelial–mesenchymal phenotype cluster (HPC) and mesenchymal phenotype cluster (MPC). Patients with gastric cancer with different EHBMT subtypes possessed distinct clinical features, molecular characteristics and prognostic outcomes. Furthermore, the proliferation ability of EPC, HPC and MPC subtypes decreases sequentially. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analysis showed that HPC subtypes are associated with inflammation and immune activation. More importantly, EHBMT discovered a sharp increase in the proportion of the HPC subtype during gastric cancer evolution. Traceability analysis indicated that the surge in HPC in gastric cancer was due to the transition from approximately 70–80% of normal EPC cases to cancerous HPC/MPC cases. In addition, the inflammatory factor IL-1β, highly expressed epithelial cells in the HPC subtype, should be a key driver for the decrease of epithelial cells by inducing EMT signaling. In conclusion, EHBMT is a novel method for visualizing cancer evolution using bulk transcriptomics. Gastric carcinogenesis is accompanied by a sharp increase in the proportion of HPC due to the abnormal EMT signaling pathway driven by an inflammatory microenvironment. Cancer development is a complex process with many differences between patients and even within a single tumor. Here researchers focused on a process called the epithelial–mesenchymal transition (EMT), which helps cancer cells spread. They developed a method to classify stomach cancer based on EMT differences using data from various sources, including RNA sequencing. This method divides cancer into three types: epithelial, hybrid and mesenchymal, each with different characteristics and outcomes. The study found that the hybrid type is more common in cancerous tissues than in normal ones. This suggests that changes in EMT are linked to cancer progression. The researchers used advanced techniques such as single-cell analysis and immunohistochemistry (a method to visualize proteins in tissues) to confirm their findings. They concluded that understanding the EMT can help predict cancer behavior and guide treatment decisions. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"EHBMT, a method for visualizing tumor evolution, identifies a surge in gastric cancer with hybrid epithelial–mesenchymal phenotypes due to an inflammatory microenvironment","authors":"Dandan Li, Zeng Zhou, Yuanjian Hui, Hedong Yu, Tao Ren, Lantian Zhai, Xinqi Li, Lin Yuan, Lingyun Xia, Weidong Leng, Shanshan Qin","doi":"10.1038/s12276-025-01570-6","DOIUrl":"10.1038/s12276-025-01570-6","url":null,"abstract":"A method for analyzing tumor evolution based on bulk RNA-sequencing data has not been reported yet. The epithelial–mesenchymal transition (EMT) is an evolutionarily conserved cellular program with high heterogeneity and plasticity. In this study, we proposed an EMT heterogeneity-based molecular typing (EHBMT) method to visualize cancer evolution and guide personalized medicine. Multiplex immunohistochemical assay and single-cell analysis were performed to confirm the feasibility of this method. EHBMT divided gastric (cancer) tissues into an epithelial phenotype cluster (EPC), hybrid epithelial–mesenchymal phenotype cluster (HPC) and mesenchymal phenotype cluster (MPC). Patients with gastric cancer with different EHBMT subtypes possessed distinct clinical features, molecular characteristics and prognostic outcomes. Furthermore, the proliferation ability of EPC, HPC and MPC subtypes decreases sequentially. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analysis showed that HPC subtypes are associated with inflammation and immune activation. More importantly, EHBMT discovered a sharp increase in the proportion of the HPC subtype during gastric cancer evolution. Traceability analysis indicated that the surge in HPC in gastric cancer was due to the transition from approximately 70–80% of normal EPC cases to cancerous HPC/MPC cases. In addition, the inflammatory factor IL-1β, highly expressed epithelial cells in the HPC subtype, should be a key driver for the decrease of epithelial cells by inducing EMT signaling. In conclusion, EHBMT is a novel method for visualizing cancer evolution using bulk transcriptomics. Gastric carcinogenesis is accompanied by a sharp increase in the proportion of HPC due to the abnormal EMT signaling pathway driven by an inflammatory microenvironment. Cancer development is a complex process with many differences between patients and even within a single tumor. Here researchers focused on a process called the epithelial–mesenchymal transition (EMT), which helps cancer cells spread. They developed a method to classify stomach cancer based on EMT differences using data from various sources, including RNA sequencing. This method divides cancer into three types: epithelial, hybrid and mesenchymal, each with different characteristics and outcomes. The study found that the hybrid type is more common in cancerous tissues than in normal ones. This suggests that changes in EMT are linked to cancer progression. The researchers used advanced techniques such as single-cell analysis and immunohistochemistry (a method to visualize proteins in tissues) to confirm their findings. They concluded that understanding the EMT can help predict cancer behavior and guide treatment decisions. 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":"2440-2457"},"PeriodicalIF":12.9,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01570-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145432872","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 : 2025-11-03DOI: 10.1038/s12276-025-01562-6
Chaimae Khaled, Mijin Kim, Booki Min
Immune responses are finely regulated by multiple mechanisms, among which immune regulatory coreceptor family molecules play a central role in both enhancing and suppressing immune responses. Traditionally, T cells have been considered the primary cell type expressing these receptors, through which their responses are modulated. This understanding led to the emergence of the field of ‘immune checkpoint blockade’, which aims to rejuvenate T cells that have become exhausted in the context of chronic infections or the tumor environments. The molecules targeted by such approaches include PD1, CTLA4, Lag3, Tim3 and TIGIT, coinhibitory receptors predominantly expressed on conventional T cells exhibiting functionally impaired, exhausted phenotypes. Interestingly, an expanding array of non-T cell types also express these receptors, although their specific roles remain largely elusive. Here we explore the immune regulatory functions of these coreceptors as expressed on non-conventional T cells, such as myeloid cells and B cells, highlighting their potential contributions to immune regulation. The immune system is a complex network of cells and molecules that protect the host from infection and disease. Dysregulation of these processes can result in pathological conditions, including chronic infections or cancer. Coinhibitory receptors such as PD1, CTLA4, Lag3, Tim3 and TIGIT are well established as key regulators of T cell-mediated immune responses. Emerging evidence indicates that these receptors are also expressed on non-T cell populations, including myeloid lineage cells and B cells, although their functional contributions in this context remain poorly understood. This review summarizes current knowledge on the expression and function of coinhibitory receptors in non-T cells and discusses how their therapeutic targeting beyond T cells may offer novel opportunities for restoring immune function in cancer and other diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"The role of coinhibitory receptor-expressing non-T cells in inflammation and immunity: unsung heroes or peripheral players?","authors":"Chaimae Khaled, Mijin Kim, Booki Min","doi":"10.1038/s12276-025-01562-6","DOIUrl":"10.1038/s12276-025-01562-6","url":null,"abstract":"Immune responses are finely regulated by multiple mechanisms, among which immune regulatory coreceptor family molecules play a central role in both enhancing and suppressing immune responses. Traditionally, T cells have been considered the primary cell type expressing these receptors, through which their responses are modulated. This understanding led to the emergence of the field of ‘immune checkpoint blockade’, which aims to rejuvenate T cells that have become exhausted in the context of chronic infections or the tumor environments. The molecules targeted by such approaches include PD1, CTLA4, Lag3, Tim3 and TIGIT, coinhibitory receptors predominantly expressed on conventional T cells exhibiting functionally impaired, exhausted phenotypes. Interestingly, an expanding array of non-T cell types also express these receptors, although their specific roles remain largely elusive. Here we explore the immune regulatory functions of these coreceptors as expressed on non-conventional T cells, such as myeloid cells and B cells, highlighting their potential contributions to immune regulation. The immune system is a complex network of cells and molecules that protect the host from infection and disease. Dysregulation of these processes can result in pathological conditions, including chronic infections or cancer. Coinhibitory receptors such as PD1, CTLA4, Lag3, Tim3 and TIGIT are well established as key regulators of T cell-mediated immune responses. Emerging evidence indicates that these receptors are also expressed on non-T cell populations, including myeloid lineage cells and B cells, although their functional contributions in this context remain poorly understood. This review summarizes current knowledge on the expression and function of coinhibitory receptors in non-T cells and discusses how their therapeutic targeting beyond T cells may offer novel opportunities for restoring immune function in cancer and other diseases. 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":"2397-2407"},"PeriodicalIF":12.9,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01562-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145432875","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 : 2025-10-29DOI: 10.1038/s12276-025-01561-7
Yena Cho, Yong Kee Kim
Coactivator-associated arginine methyltransferase 1 (CARM1), first identified in 1999, has been studied primarily for its nuclear role in epigenetic regulation through histone methylation. Subsequent research has expanded the substrate repertoire to include nonhistone proteins, thus uncovering broader functions in maintaining cellular homeostasis by regulating transcription, RNA processing, metabolism and organelle dynamics. More recently, CARM1 was shown to exert scaffolding functions independent of its catalytic activity, thereby orchestrating key signaling events involved in transcriptional activation, replication stress response and cell cycle control. These findings highlight the multifaceted roles of CARM1 in nuclear and cytoplasmic compartments. Despite substantial progress in the development of selective small-molecule inhibitors, their inability to target noncatalytic functions has limited their therapeutic potential. Consequently, novel strategies, such as proteolysis-targeting chimeras, are being explored to degrade the entire CARM1 protein, thereby abolishing its enzymatic and scaffolding functions. Here this review outlines the evolving functional landscape of CARM1, from its roles as a transcriptional coactivator to a multifunctional regulator of cellular homeostasis, with an emphasis on its enzyme-independent functions, thereby providing novel insights for next-generation therapeutic strategies. Arginine methylation is a key process in cells, affecting many functions such as gene expression and DNA repair. This study focuses on CARM1, an enzyme involved in this process. Researchers explored the roles of CARM1 beyond its known nuclear functions. They used various experiments, including studies on mice, to understand how CARM1 works in different parts of the cell. CARM1 was initially known for modifying histones to regulate genes. However, it also affects other proteins outside the nucleus, influencing processes such as metabolism and cell structure. The study found that CARM1 can act without its enzyme activity, serving as a scaffold to support other cellular functions. The research highlights the potential of CARM1 as a target for treating diseases such as cancer. By developing inhibitors and new technologies such as proteolysis-targeting chimeras, scientists aim to block both its enzymatic and nonenzymatic roles. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Multifaceted roles of CARM1 beyond histone arginine methylation","authors":"Yena Cho, Yong Kee Kim","doi":"10.1038/s12276-025-01561-7","DOIUrl":"10.1038/s12276-025-01561-7","url":null,"abstract":"Coactivator-associated arginine methyltransferase 1 (CARM1), first identified in 1999, has been studied primarily for its nuclear role in epigenetic regulation through histone methylation. Subsequent research has expanded the substrate repertoire to include nonhistone proteins, thus uncovering broader functions in maintaining cellular homeostasis by regulating transcription, RNA processing, metabolism and organelle dynamics. More recently, CARM1 was shown to exert scaffolding functions independent of its catalytic activity, thereby orchestrating key signaling events involved in transcriptional activation, replication stress response and cell cycle control. These findings highlight the multifaceted roles of CARM1 in nuclear and cytoplasmic compartments. Despite substantial progress in the development of selective small-molecule inhibitors, their inability to target noncatalytic functions has limited their therapeutic potential. Consequently, novel strategies, such as proteolysis-targeting chimeras, are being explored to degrade the entire CARM1 protein, thereby abolishing its enzymatic and scaffolding functions. Here this review outlines the evolving functional landscape of CARM1, from its roles as a transcriptional coactivator to a multifunctional regulator of cellular homeostasis, with an emphasis on its enzyme-independent functions, thereby providing novel insights for next-generation therapeutic strategies. Arginine methylation is a key process in cells, affecting many functions such as gene expression and DNA repair. This study focuses on CARM1, an enzyme involved in this process. Researchers explored the roles of CARM1 beyond its known nuclear functions. They used various experiments, including studies on mice, to understand how CARM1 works in different parts of the cell. CARM1 was initially known for modifying histones to regulate genes. However, it also affects other proteins outside the nucleus, influencing processes such as metabolism and cell structure. The study found that CARM1 can act without its enzyme activity, serving as a scaffold to support other cellular functions. The research highlights the potential of CARM1 as a target for treating diseases such as cancer. By developing inhibitors and new technologies such as proteolysis-targeting chimeras, scientists aim to block both its enzymatic and nonenzymatic roles. 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 10","pages":"2251-2263"},"PeriodicalIF":12.9,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01561-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145394885","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 : 2025-10-29DOI: 10.1038/s12276-025-01566-2
Hui Dang, Yan Liu, Ye Zhou, Mengjun Sui, Yubo Wang, Wei Qiang, Fang Sui, Yan Zhang, Hongxin Cao, Xiaoyan Wu, Meiju Ji, Peng Hou
Ten eleven translocation 1 (TET1) is a 5-methylcytosine dioxygenase, and its altered DNA demethylation has been implicated in human diseases. However, its role in regulating thyroid function remains totally unknown. Here we first generated thyroid-specific Tet1 knockout combined with thyroid-specific BrafV600E transgenic mouse model (Thy-BrafV600E; Tet1−/−) and their control mice (Thy-BrafV600E; Tet1+/+). The latter developed severe hypothyroidism and lost reproductive ability owing to structural damages of thyroid gland, while thyroid-specific Tet1 knockout effectively restored thyroid structure and function of Thy-BrafV600E; Tet1+/+ mice and their reproductive ability. In addition, we also established thyroid-specific Tet1 knockout mouse model (Thy-Tet1−/−) and demonstrated that these mice could develop hyperthyroidism with systemic hypermetabolic symptoms such as weight loss, increased heart rate and elevated systolic blood pressure, further supporting the inhibitory effect of TET1 on thyroid function. Transcriptomic sequencing revealed that key genes related to metabolism and synthesis of thyroid hormones such as PAX8, SLC5A5 and TPO were significantly upregulated in Thy-Tet1−/− mice. Mechanistically, TET1 recruits HDAC1 to reduce the levels of H3K27Ac and H3K9Ac in the PAX8 promoter, thereby inhibiting the expression of itself and its downstream targets NIS and TPO. Further studies showed that elevated miR-29c-3p in serum exosomes enhanced thyroid function by targeting TET1, which may be one of the causes of hyperthyroidism. Thus, this study uncovers a new mechanism by which TET1 suppresses thyroid function, providing a new perspective to explore the pathogenesis of hyperthyroidism. Hyperthyroidism is a condition in which the thyroid gland produces too many hormones, leading to symptoms such as weight loss and irritability. Here scientists are exploring the role of a protein called TET1 in thyroid function. TET1 is known for its role in modifying DNA, which can affect how genes are turned on or off. In this study, researchers investigated whether TET1 influences thyroid activity. They used mice that were genetically modified to lack TET1 specifically in their thyroid glands. These mice showed signs of hyperthyroidism such as increased thyroid hormone levels and faster metabolism. The researchers found that TET1 normally helps suppress the activity of certain genes involved in thyroid hormone production by interacting with other proteins that modify DNA structure. This study suggests that TET1 plays a crucial role in regulating thyroid function and that its absence can lead to hyperthyroidism. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"TET1 loss propels the development of hyperthyroidism by remodeling histone modifications of PAX8 promoter","authors":"Hui Dang, Yan Liu, Ye Zhou, Mengjun Sui, Yubo Wang, Wei Qiang, Fang Sui, Yan Zhang, Hongxin Cao, Xiaoyan Wu, Meiju Ji, Peng Hou","doi":"10.1038/s12276-025-01566-2","DOIUrl":"10.1038/s12276-025-01566-2","url":null,"abstract":"Ten eleven translocation 1 (TET1) is a 5-methylcytosine dioxygenase, and its altered DNA demethylation has been implicated in human diseases. However, its role in regulating thyroid function remains totally unknown. Here we first generated thyroid-specific Tet1 knockout combined with thyroid-specific BrafV600E transgenic mouse model (Thy-BrafV600E; Tet1−/−) and their control mice (Thy-BrafV600E; Tet1+/+). The latter developed severe hypothyroidism and lost reproductive ability owing to structural damages of thyroid gland, while thyroid-specific Tet1 knockout effectively restored thyroid structure and function of Thy-BrafV600E; Tet1+/+ mice and their reproductive ability. In addition, we also established thyroid-specific Tet1 knockout mouse model (Thy-Tet1−/−) and demonstrated that these mice could develop hyperthyroidism with systemic hypermetabolic symptoms such as weight loss, increased heart rate and elevated systolic blood pressure, further supporting the inhibitory effect of TET1 on thyroid function. Transcriptomic sequencing revealed that key genes related to metabolism and synthesis of thyroid hormones such as PAX8, SLC5A5 and TPO were significantly upregulated in Thy-Tet1−/− mice. Mechanistically, TET1 recruits HDAC1 to reduce the levels of H3K27Ac and H3K9Ac in the PAX8 promoter, thereby inhibiting the expression of itself and its downstream targets NIS and TPO. Further studies showed that elevated miR-29c-3p in serum exosomes enhanced thyroid function by targeting TET1, which may be one of the causes of hyperthyroidism. Thus, this study uncovers a new mechanism by which TET1 suppresses thyroid function, providing a new perspective to explore the pathogenesis of hyperthyroidism. Hyperthyroidism is a condition in which the thyroid gland produces too many hormones, leading to symptoms such as weight loss and irritability. Here scientists are exploring the role of a protein called TET1 in thyroid function. TET1 is known for its role in modifying DNA, which can affect how genes are turned on or off. In this study, researchers investigated whether TET1 influences thyroid activity. They used mice that were genetically modified to lack TET1 specifically in their thyroid glands. These mice showed signs of hyperthyroidism such as increased thyroid hormone levels and faster metabolism. The researchers found that TET1 normally helps suppress the activity of certain genes involved in thyroid hormone production by interacting with other proteins that modify DNA structure. This study suggests that TET1 plays a crucial role in regulating thyroid function and that its absence can lead to hyperthyroidism. 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 10","pages":"2376-2392"},"PeriodicalIF":12.9,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01566-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145394912","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 : 2025-10-27DOI: 10.1038/s12276-025-01548-4
Sunil S. Adav, Kee Woei Ng
Hair specimens are vital in precision medicine, forensics and environmental monitoring owing to their ability to retain biochemical data over time. Their noninvasive collection and long-term storage suitability make them ideal for diagnostics and investigations, offering historical insights into health and exposure records. In medicine, hair analysis provides a long-term biochemical profile, aiding in monitoring health conditions, nutritional deficiencies, toxin exposure and treatment efficacy. Advances in mass spectrometry, chromatography and spectroscopy have expanded their applications to cancer diagnostics, tuberculosis, HIV, neurological disorders and mental health assessments. In forensic science, the resistance of hair to decomposition and its ability to absorb substances help identify individuals, detect drug use and reconstruct crime scenes. Omics techniques such as genomics, proteomics and metabolomics enhance forensic accuracy by enabling precise substance detection and timeline reconstruction. Despite its potential, challenges such as hair growth variability, contamination and lack of standardized techniques limit the current impact of hair analysis. Addressing these issues could advance its role in diagnostics and forensic investigations. This review explores recent advancements and applications of hair analysis in precision medicine, infectious diseases, mental health, stress assessment and forensic science. Hair is a simple yet valuable sample used in many fields such as medicine, cosmetics and forensics. It is easy to collect and store, making it useful for studying diseases and environmental exposures. This study aims to address how hair can be better used in precision medicine and diagnostics. Researchers have found that hair can help detect diseases such as cancer and monitor drug levels in patients. They use advanced techniques including mass spectrometry (a method to measure molecules) to analyze hair samples. This helps in understanding how drugs are absorbed and how diseases progress over time. Hair analysis can also reveal exposure to toxins and stress levels by measuring substances stored in the hair over months. The study concludes that hair is a promising tool for personalized healthcare, offering insights into long-term health conditions. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"The multifaceted role of hair as a biospecimen: recent advances in precision medicine and forensic science","authors":"Sunil S. Adav, Kee Woei Ng","doi":"10.1038/s12276-025-01548-4","DOIUrl":"10.1038/s12276-025-01548-4","url":null,"abstract":"Hair specimens are vital in precision medicine, forensics and environmental monitoring owing to their ability to retain biochemical data over time. Their noninvasive collection and long-term storage suitability make them ideal for diagnostics and investigations, offering historical insights into health and exposure records. In medicine, hair analysis provides a long-term biochemical profile, aiding in monitoring health conditions, nutritional deficiencies, toxin exposure and treatment efficacy. Advances in mass spectrometry, chromatography and spectroscopy have expanded their applications to cancer diagnostics, tuberculosis, HIV, neurological disorders and mental health assessments. In forensic science, the resistance of hair to decomposition and its ability to absorb substances help identify individuals, detect drug use and reconstruct crime scenes. Omics techniques such as genomics, proteomics and metabolomics enhance forensic accuracy by enabling precise substance detection and timeline reconstruction. Despite its potential, challenges such as hair growth variability, contamination and lack of standardized techniques limit the current impact of hair analysis. Addressing these issues could advance its role in diagnostics and forensic investigations. This review explores recent advancements and applications of hair analysis in precision medicine, infectious diseases, mental health, stress assessment and forensic science. Hair is a simple yet valuable sample used in many fields such as medicine, cosmetics and forensics. It is easy to collect and store, making it useful for studying diseases and environmental exposures. This study aims to address how hair can be better used in precision medicine and diagnostics. Researchers have found that hair can help detect diseases such as cancer and monitor drug levels in patients. They use advanced techniques including mass spectrometry (a method to measure molecules) to analyze hair samples. This helps in understanding how drugs are absorbed and how diseases progress over time. Hair analysis can also reveal exposure to toxins and stress levels by measuring substances stored in the hair over months. The study concludes that hair is a promising tool for personalized healthcare, offering insights into long-term health conditions. 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 10","pages":"2234-2250"},"PeriodicalIF":12.9,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01548-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145379775","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 : 2025-10-23DOI: 10.1038/s12276-025-01563-5
Jong-Won Kim, Mengyun Ke, Donovan Whitfield, Bin Yang, Gu Seob Roh, Wen Xie
Cysteine (Cys) posttranslational modifications play a critical role in regulating protein function, cellular signaling and redox homeostasis in various physiological and pathological conditions. Sulfiredoxin-1 (SRXN1) has emerged as a key regulator of protein redox homeostasis through its involvement in Cys sulfinylation. However, the role of SRXN1 in the pathogenesis of diseases and its therapeutic implications have yet to be fully explored. Beyond its classical function in reactive oxygen species detoxification, SRXN1 also modulates redox-sensitive signaling pathways that govern inflammation, apoptosis and cell survival, making it an essential component of cellular defense against oxidative stress-related damage. Here we highlight the significance of SRXN1 in regulating Cys sulfinylation across a broad spectrum of liver diseases. Furthermore, we emphasize the critical role of SRXN1 in regulating oxidative stress and cellular signaling through its interaction and desulfinylation of target or substrate proteins, both of which are crucial to maintaining cellular function under pathological conditions. Finally, we discuss the potential therapeutic implications of targeting SRXN1 in disease contexts where oxidative stress exacerbates pathological processes. A deeper understanding of SRXN1-mediated redox regulation may offer a novel therapeutic avenue to mitigate Cys oxidation and improve clinical outcomes in various liver disease contexts. Oxidative stress, an imbalance between harmful molecules called reactive oxygen species and the body’s defenses, contributes to many diseases. A key player in managing this stress is a protein called sulfiredoxin 1 (SRXN1). SRXN1 helps to repair proteins damaged by reactive oxygen species, particularly by reversing a process called cysteine sulfinylation, which can impair protein function. This Review explores SRXN1’s role in liver diseases, highlighting its protective effects on hepatocytes under pathological conditions such as acute liver injury, alcoholic liver disease and liver fibrosis. It does this by maintaining redox balance. Researchers used various methods to study SRXN1’s effects, including examining its interactions with other proteins and its impact on cell survival. Results show that, while SRXN1 protects against liver damage, it also aids cancer cell survival in liver cancer. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Redox regulation by sulfiredoxin-1: bridging cysteine oxidation and liver disease therapeutics","authors":"Jong-Won Kim, Mengyun Ke, Donovan Whitfield, Bin Yang, Gu Seob Roh, Wen Xie","doi":"10.1038/s12276-025-01563-5","DOIUrl":"10.1038/s12276-025-01563-5","url":null,"abstract":"Cysteine (Cys) posttranslational modifications play a critical role in regulating protein function, cellular signaling and redox homeostasis in various physiological and pathological conditions. Sulfiredoxin-1 (SRXN1) has emerged as a key regulator of protein redox homeostasis through its involvement in Cys sulfinylation. However, the role of SRXN1 in the pathogenesis of diseases and its therapeutic implications have yet to be fully explored. Beyond its classical function in reactive oxygen species detoxification, SRXN1 also modulates redox-sensitive signaling pathways that govern inflammation, apoptosis and cell survival, making it an essential component of cellular defense against oxidative stress-related damage. Here we highlight the significance of SRXN1 in regulating Cys sulfinylation across a broad spectrum of liver diseases. Furthermore, we emphasize the critical role of SRXN1 in regulating oxidative stress and cellular signaling through its interaction and desulfinylation of target or substrate proteins, both of which are crucial to maintaining cellular function under pathological conditions. Finally, we discuss the potential therapeutic implications of targeting SRXN1 in disease contexts where oxidative stress exacerbates pathological processes. A deeper understanding of SRXN1-mediated redox regulation may offer a novel therapeutic avenue to mitigate Cys oxidation and improve clinical outcomes in various liver disease contexts. Oxidative stress, an imbalance between harmful molecules called reactive oxygen species and the body’s defenses, contributes to many diseases. A key player in managing this stress is a protein called sulfiredoxin 1 (SRXN1). SRXN1 helps to repair proteins damaged by reactive oxygen species, particularly by reversing a process called cysteine sulfinylation, which can impair protein function. This Review explores SRXN1’s role in liver diseases, highlighting its protective effects on hepatocytes under pathological conditions such as acute liver injury, alcoholic liver disease and liver fibrosis. It does this by maintaining redox balance. Researchers used various methods to study SRXN1’s effects, including examining its interactions with other proteins and its impact on cell survival. Results show that, while SRXN1 protects against liver damage, it also aids cancer cell survival in liver cancer. 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 10","pages":"2226-2233"},"PeriodicalIF":12.9,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01563-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145356722","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 : 2025-10-23DOI: 10.1038/s12276-025-01558-2
Kang-Min Lee, Jihun Kim, Hye Lim Jung, Young Yeon Kim, Jihoon Lee, Yeon-Ju Lee, Eunhee Yoo, Hyi-Seung Lee, Jeanho Yun
Mitophagy has been implicated in kidney function and related diseases. However, a direct analysis of mitophagy in kidney models, including disease models, remains notably lacking. Here we analyzed mitophagy levels in Drosophila Malpighian tubules, a functional analog of the human kidney, using a transgenic model of the engineered mitophagy reporter mt-Keima. We found that mitophagy is highly active in the major cell types of the Malpighian tubules, including renal stem cells, principal cells and stellate cells. Notably, the suppression of mitophagy by genetic downregulation of mitophagy-related genes, such as ATG5 and ULK1, led to a significant decrease in the secretion function of the Malpighian tubules, suggesting that mitophagy is essential for their proper function. Interestingly, a continuous high-sugar diet, which is used as a model for diabetic kidney disease, caused a reduction in mitophagy levels in principal cells before the development of mitochondrial dysfunction and defective secretion. Importantly, stimulation of mitophagy with the recently developed mitophagy inducer PDE701 rescued both mitochondrial dysfunction and defective phenotypes in a diabetic kidney disease model. Our results highlight the pivotal role of mitophagy in kidney function and suggest that modulating mitophagy could be a potential strategy for treating kidney diseases. Mitophagy is a process that removes damaged mitochondria to keep cells healthy. This study looks at how mitophagy works in the kidneys using fruit flies, which have similar kidney-like structures called Malpighian tubules. Here researchers used a special protein called mt-Keima to measure mitophagy in these tubules. They found that mitophagy is crucial for the function of the tubules. When mitophagy was reduced, the tubules did not work well, especially under conditions mimicking diabetic kidney disease (DKD). The study used a high-sugar diet to create a DKD model in flies, which led to decreased mitophagy and kidney dysfunction. However, a new compound called PDE701 increased mitophagy and improved kidney function in these flies. The findings suggest that boosting mitophagy could help treat kidney diseases such as DKD. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Exploring mitophagy levels in Drosophila Malpighian tubules unveils the pivotal role of mitophagy in kidney function and diabetic kidney disease","authors":"Kang-Min Lee, Jihun Kim, Hye Lim Jung, Young Yeon Kim, Jihoon Lee, Yeon-Ju Lee, Eunhee Yoo, Hyi-Seung Lee, Jeanho Yun","doi":"10.1038/s12276-025-01558-2","DOIUrl":"10.1038/s12276-025-01558-2","url":null,"abstract":"Mitophagy has been implicated in kidney function and related diseases. However, a direct analysis of mitophagy in kidney models, including disease models, remains notably lacking. Here we analyzed mitophagy levels in Drosophila Malpighian tubules, a functional analog of the human kidney, using a transgenic model of the engineered mitophagy reporter mt-Keima. We found that mitophagy is highly active in the major cell types of the Malpighian tubules, including renal stem cells, principal cells and stellate cells. Notably, the suppression of mitophagy by genetic downregulation of mitophagy-related genes, such as ATG5 and ULK1, led to a significant decrease in the secretion function of the Malpighian tubules, suggesting that mitophagy is essential for their proper function. Interestingly, a continuous high-sugar diet, which is used as a model for diabetic kidney disease, caused a reduction in mitophagy levels in principal cells before the development of mitochondrial dysfunction and defective secretion. Importantly, stimulation of mitophagy with the recently developed mitophagy inducer PDE701 rescued both mitochondrial dysfunction and defective phenotypes in a diabetic kidney disease model. Our results highlight the pivotal role of mitophagy in kidney function and suggest that modulating mitophagy could be a potential strategy for treating kidney diseases. Mitophagy is a process that removes damaged mitochondria to keep cells healthy. This study looks at how mitophagy works in the kidneys using fruit flies, which have similar kidney-like structures called Malpighian tubules. Here researchers used a special protein called mt-Keima to measure mitophagy in these tubules. They found that mitophagy is crucial for the function of the tubules. When mitophagy was reduced, the tubules did not work well, especially under conditions mimicking diabetic kidney disease (DKD). The study used a high-sugar diet to create a DKD model in flies, which led to decreased mitophagy and kidney dysfunction. However, a new compound called PDE701 increased mitophagy and improved kidney function in these flies. The findings suggest that boosting mitophagy could help treat kidney diseases such as DKD. 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 10","pages":"2364-2375"},"PeriodicalIF":12.9,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01558-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145356655","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 : 2025-10-14DOI: 10.1038/s12276-025-01560-8
Youngsuk Seo, Ji Eun Park, Jae Young Yu, Boyoung Lee, Jong Hyuk Yoon, Hyun Joo An
Glycosylation functions as a pivotal posttranslational modification in proteins and as a distinct biosynthetic process in lipids. In the brain, it plays essential roles in development, function and homeostasis by modulating protein folding, receptor trafficking and intercellular communication. Although glycans constitute less than 1% of the brain’s mass, their impact is disproportionately profound. Recent technological advances have uncovered the essential contributions of both protein- and lipid-bound glycans, including N-glycans, O-glycans and gangliosides, to brain physiology and disease. Here we explore the emerging landscape of brain glycosylation, highlighting its distinct roles in neurodevelopment, synaptic organization and immune regulation. Aberrant glycosylation has been implicated in neurodegenerative diseases (for example, Alzheimer’s and Parkinson’s), psychiatric disorders (for example, depression and schizophrenia) and neurodevelopmental conditions (for example, autism spectrum disorders, attention deficit hyperactivity disorder and dystroglycanopathies). We summarize recent breakthroughs in glycomics technologies, including glycan enrichment, liquid chromatography–tandem mass spectrometry, MALDI-based imaging mass spectrometry and high-throughput omics, which enable molecular and spatial mapping of brain glycosylation. Artificial-intelligence-driven bioinformatics and multi-omics integration are rapidly opening new avenues for deciphering glycan-mediated regulation in brain health and disease. Together, these developments position brain glycosylation as a transformative frontier in neuroscience, with the potential to yield novel diagnostic biomarkers and therapeutic strategies for complex brain disorders. The human brain is a complex organ with over 100 billion cells, including neurons and glial cells. It controls thoughts, emotions and actions through intricate communication systems. This Review explores glycosylation, a process where sugars attach to proteins and lipids, which is crucial for brain function but not well understood. Researchers have used advanced techniques such as mass spectrometry to study glycosylation in the brain. Studies have shown that glycosylation influences brain development, neuronal communication and disease mechanisms. For example, changes in glycosylation have been associated with Alzheimer’s and Parkinson’s diseases. The study highlights the importance of understanding glycosylation for developing new treatments. The researchers conclude that glycosylation is a key player in brain health and disease. Future research could lead to new diagnostic tools and therapies for brain disorders by focusing on glycosylation patterns. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"The emerging landscape of brain glycosylation: from molecular complexity to therapeutic potential","authors":"Youngsuk Seo, Ji Eun Park, Jae Young Yu, Boyoung Lee, Jong Hyuk Yoon, Hyun Joo An","doi":"10.1038/s12276-025-01560-8","DOIUrl":"10.1038/s12276-025-01560-8","url":null,"abstract":"Glycosylation functions as a pivotal posttranslational modification in proteins and as a distinct biosynthetic process in lipids. In the brain, it plays essential roles in development, function and homeostasis by modulating protein folding, receptor trafficking and intercellular communication. Although glycans constitute less than 1% of the brain’s mass, their impact is disproportionately profound. Recent technological advances have uncovered the essential contributions of both protein- and lipid-bound glycans, including N-glycans, O-glycans and gangliosides, to brain physiology and disease. Here we explore the emerging landscape of brain glycosylation, highlighting its distinct roles in neurodevelopment, synaptic organization and immune regulation. Aberrant glycosylation has been implicated in neurodegenerative diseases (for example, Alzheimer’s and Parkinson’s), psychiatric disorders (for example, depression and schizophrenia) and neurodevelopmental conditions (for example, autism spectrum disorders, attention deficit hyperactivity disorder and dystroglycanopathies). We summarize recent breakthroughs in glycomics technologies, including glycan enrichment, liquid chromatography–tandem mass spectrometry, MALDI-based imaging mass spectrometry and high-throughput omics, which enable molecular and spatial mapping of brain glycosylation. Artificial-intelligence-driven bioinformatics and multi-omics integration are rapidly opening new avenues for deciphering glycan-mediated regulation in brain health and disease. Together, these developments position brain glycosylation as a transformative frontier in neuroscience, with the potential to yield novel diagnostic biomarkers and therapeutic strategies for complex brain disorders. The human brain is a complex organ with over 100 billion cells, including neurons and glial cells. It controls thoughts, emotions and actions through intricate communication systems. This Review explores glycosylation, a process where sugars attach to proteins and lipids, which is crucial for brain function but not well understood. Researchers have used advanced techniques such as mass spectrometry to study glycosylation in the brain. Studies have shown that glycosylation influences brain development, neuronal communication and disease mechanisms. For example, changes in glycosylation have been associated with Alzheimer’s and Parkinson’s diseases. The study highlights the importance of understanding glycosylation for developing new treatments. The researchers conclude that glycosylation is a key player in brain health and disease. Future research could lead to new diagnostic tools and therapies for brain disorders by focusing on glycosylation patterns. 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 10","pages":"2214-2225"},"PeriodicalIF":12.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01560-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145294367","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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