Pub Date : 2026-01-21DOI: 10.1038/s12276-025-01629-4
Bing-Yao Liu, Xing-Dong Chen, Hui-Lin Liu, Si-Wei Wang, Qian-Zhong Song, Hui Cheng, Sen Li, Hai-Yan Wang, Xiu-Min Lu, Yong-Tang Wang
The pathophysiology of post-traumatic stress disorder (PTSD) shows notable associations with compromised hippocampal neurophysiology. Notwithstanding ongoing debates, PTBP1 knockdown (KD) demonstrates the capacity to drive glia-to-neuron reprogramming, potentially offering therapeutic benefits for some neurodegenerative pathologies. However, PTBP1 KD can upregulate the expression of Nogo-A by alternative splicing, triggering the inhibition of nerve regeneration. Currently, the role of PTBP1 in PTSD remains unknown. Here we sought to elucidate the neurorestorative effects of modulating the PTBP1/Nogo-A/NgR axis in a mouse model of PTSD established through the single prolonged stress paradigm, and the mechanisms were further investigated through a series of experiments including pathological and molecular detection. The results indicated that PTBP1 KD ameliorates PTSD-like behaviors in mice by balancing Bcl-2/Bax expression and suppressing Caspase-3 splicing activation to inhibit hippocampal neuronal apoptosis, enhancing synaptic plasticity through upregulating PSD95 and SYN1, increasing dendritic spine density and stabilizing axonal architecture via elevated NF200 expression. However, compared with single prolonged stress alone, PTBP1 KD potentiates the activation of Nogo-A/NgR pathway, adversely impacting both dendritic morphology and axonal elongation. Therefore, we proposed a combined KD of PTBP1 and NgR to counteract the adverse effects mediated by Nogo-A signal activation, effectively promoting dendritic growth and axonal extension in hippocampal neurons of PTSD mice. Our findings underscore the potential and limitations of PTBP1 as a therapeutic target and propose a novel method for PTSD treatment through combined target intervention of PTBP1 and NgR. This study provides a theoretical foundation for multitarget intervention strategies in the treatment of PTSD and related disorders. Post-traumatic stress disorder (PTSD) is a mental health condition that can develop after experiencing a traumatic event. This study investigates the role of a protein called PTBP1 in PTSD. Researchers used a type of virus to reduce PTBP1 levels in the brains of mice with PTSD-like symptoms. They found that lowering PTBP1 improved the mice’s behavior, reducing fear and anxiety. Results showed that reducing PTBP1 helped protect brain cells from dying and improved connections between neurons. However, it also activated a pathway that could hinder nerve growth. To address this, the researchers also targeted another protein, NgR, which helped counteract the negative effects. In conclusion, targeting PTBP1 and NgR together may offer a new approach to treating PTSD by improving brain function while minimizing side effects. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"The therapeutic potential and mechanisms of targeting the PTBP1/Nogo-A/NgR axis in PTSD induced by single prolonged stress in mice","authors":"Bing-Yao Liu, Xing-Dong Chen, Hui-Lin Liu, Si-Wei Wang, Qian-Zhong Song, Hui Cheng, Sen Li, Hai-Yan Wang, Xiu-Min Lu, Yong-Tang Wang","doi":"10.1038/s12276-025-01629-4","DOIUrl":"10.1038/s12276-025-01629-4","url":null,"abstract":"The pathophysiology of post-traumatic stress disorder (PTSD) shows notable associations with compromised hippocampal neurophysiology. Notwithstanding ongoing debates, PTBP1 knockdown (KD) demonstrates the capacity to drive glia-to-neuron reprogramming, potentially offering therapeutic benefits for some neurodegenerative pathologies. However, PTBP1 KD can upregulate the expression of Nogo-A by alternative splicing, triggering the inhibition of nerve regeneration. Currently, the role of PTBP1 in PTSD remains unknown. Here we sought to elucidate the neurorestorative effects of modulating the PTBP1/Nogo-A/NgR axis in a mouse model of PTSD established through the single prolonged stress paradigm, and the mechanisms were further investigated through a series of experiments including pathological and molecular detection. The results indicated that PTBP1 KD ameliorates PTSD-like behaviors in mice by balancing Bcl-2/Bax expression and suppressing Caspase-3 splicing activation to inhibit hippocampal neuronal apoptosis, enhancing synaptic plasticity through upregulating PSD95 and SYN1, increasing dendritic spine density and stabilizing axonal architecture via elevated NF200 expression. However, compared with single prolonged stress alone, PTBP1 KD potentiates the activation of Nogo-A/NgR pathway, adversely impacting both dendritic morphology and axonal elongation. Therefore, we proposed a combined KD of PTBP1 and NgR to counteract the adverse effects mediated by Nogo-A signal activation, effectively promoting dendritic growth and axonal extension in hippocampal neurons of PTSD mice. Our findings underscore the potential and limitations of PTBP1 as a therapeutic target and propose a novel method for PTSD treatment through combined target intervention of PTBP1 and NgR. This study provides a theoretical foundation for multitarget intervention strategies in the treatment of PTSD and related disorders. Post-traumatic stress disorder (PTSD) is a mental health condition that can develop after experiencing a traumatic event. This study investigates the role of a protein called PTBP1 in PTSD. Researchers used a type of virus to reduce PTBP1 levels in the brains of mice with PTSD-like symptoms. They found that lowering PTBP1 improved the mice’s behavior, reducing fear and anxiety. Results showed that reducing PTBP1 helped protect brain cells from dying and improved connections between neurons. However, it also activated a pathway that could hinder nerve growth. To address this, the researchers also targeted another protein, NgR, which helped counteract the negative effects. In conclusion, targeting PTBP1 and NgR together may offer a new approach to treating PTSD by improving brain function while minimizing side effects. 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":"58 1","pages":"211-226"},"PeriodicalIF":12.9,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01629-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146020636","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 : 2026-01-16DOI: 10.1038/s12276-025-01624-9
Sudeep Khadka, Hee-Young Jeon, Arif Hussain, Jianfei Qi
Androgen receptor (AR) overexpression is a key mechanism driving the development of castration-resistant prostate cancer (CRPC). This can result from multiple factors, including enhanced AR transcription and increased stability of AR mRNA and protein. In clinical CRPC samples, one cause of AR overexpression is gene amplification at the AR locus, which leads to elevated AR transcript and protein levels. In addition, increased activity or copy number of enhancer elements near the AR gene has been associated with elevated AR transcription. These regulatory regions interact with the AR gene promoter through enhancer–promoter looping, thereby enhancing AR mRNA transcription. Elucidating the role of these enhancer elements in driving AR overexpression and aberrant AR signaling may uncover new therapeutic targets for CRPC. Prostate cancer is a major health issue for men worldwide, with advanced stages being particularly deadly. The review focuses on understanding why some prostate cancers become resistant to current treatments. Researchers explored how certain parts of the DNA near the androgen receptor (AR) gene contribute to this resistance. The studies used various techniques to examine prostate cancer cells and tissues. They identified specific DNA regions, called enhancers, that boost AR gene transcription. These enhancers can become more active or increase in number, leading to higher AR levels, which helps cancer resist treatment. Key findings show that these enhancers, when amplified or activated, significantly increase AR expression. This contributes to treatment resistance in advanced prostate cancer. The researchers suggest that targeting these enhancers could offer new ways to treat resistant prostate cancer.
{"title":"Regulation of androgen receptor expression by enhancer elements in prostate cancer","authors":"Sudeep Khadka, Hee-Young Jeon, Arif Hussain, Jianfei Qi","doi":"10.1038/s12276-025-01624-9","DOIUrl":"10.1038/s12276-025-01624-9","url":null,"abstract":"Androgen receptor (AR) overexpression is a key mechanism driving the development of castration-resistant prostate cancer (CRPC). This can result from multiple factors, including enhanced AR transcription and increased stability of AR mRNA and protein. In clinical CRPC samples, one cause of AR overexpression is gene amplification at the AR locus, which leads to elevated AR transcript and protein levels. In addition, increased activity or copy number of enhancer elements near the AR gene has been associated with elevated AR transcription. These regulatory regions interact with the AR gene promoter through enhancer–promoter looping, thereby enhancing AR mRNA transcription. Elucidating the role of these enhancer elements in driving AR overexpression and aberrant AR signaling may uncover new therapeutic targets for CRPC. Prostate cancer is a major health issue for men worldwide, with advanced stages being particularly deadly. The review focuses on understanding why some prostate cancers become resistant to current treatments. Researchers explored how certain parts of the DNA near the androgen receptor (AR) gene contribute to this resistance. The studies used various techniques to examine prostate cancer cells and tissues. They identified specific DNA regions, called enhancers, that boost AR gene transcription. These enhancers can become more active or increase in number, leading to higher AR levels, which helps cancer resist treatment. Key findings show that these enhancers, when amplified or activated, significantly increase AR expression. This contributes to treatment resistance in advanced prostate cancer. The researchers suggest that targeting these enhancers could offer new ways to treat resistant prostate cancer.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"58 1","pages":"94-98"},"PeriodicalIF":12.9,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01624-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145991604","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 : 2026-01-16DOI: 10.1038/s12276-025-01621-y
Koung Li Kim, Minju Kim, Yubin Hwang, Duk-Kyung Kim, Jeongmin Kim, June Hyeok Lee, Yong-Wook Son, Jae-Hyung Jang, Kyung-Sun Heo, Misato Iwashita, Yoichi Kosodo, Wonhee Suh
Marfan syndrome (MFS), caused by mutations in the FBN1 gene, predisposes individuals to thoracic aortic aneurysm (TAA), a life-threatening complication. Recent studies have suggested that dysregulated mechanosignaling in aortic smooth muscle cells (SMCs) plays a pivotal role in TAA pathogenesis in MFS. However, the key molecular drivers remain largely undefined. Here we identify fibroblast growth factor 12 (FGF12) as a novel mediator of aberrant mechanosignaling in aortic SMCs during TAA formation in MFS. FGF12 is markedly upregulated in aortic SMCs of thoracic aneurysmal aortas from Fbn1C1039G/+ MFS mice and from patients with MFS. Mechanistically, FGF12 expression is induced by transforming growth factor-β/SMAD signaling and by cyclic mechanical stretch in aortic SMCs. FGF12 upregulates the expression of angiotensin II (AngII) and AngII type 1 receptor (AT1R), thereby activating the AngII/AT1R signaling pathway. FGF12-induced AT1R activation promotes aberrant mechanosignaling, as indicated by increased RhoA-GTP levels, stress fiber formation, focal adhesion assembly and focal adhesion kinase phosphorylation, ultimately leading to increased aortic SMC stiffness. In vivo studies using Fgf12 heterozygous (Fgf12+/−) mice reveal that Fgf12 haploinsufficiency significantly ameliorates AngII/β-aminopropionitrile-induced TAA formation, accompanied by reduced AT1R signaling and attenuation of aberrant mechanosignaling in the thoracic aortas. Furthermore, in Fbn1C1039G/+ MFS mice, Fgf12 haploinsufficiency (Fgf12+/−Fbn1C1039G/+) substantially mitigates TAA progression and arterial stiffening, while alleviating dysregulated mechanosignaling in thoracic aortic SMCs. Collectively, these findings identify FGF12 as a critical regulator of aberrant mechanosignaling in aortic SMCs and a key contributor to TAA formation in MFS. Marfan syndrome is a genetic disorder affecting connective tissue, often leading to dangerous aortic problems. This study explores how a protein called FGF12 might contribute to these issues. Researchers found that FGF12 is more active in the aortas of people with Marfan syndrome, which could worsen aortic problems. They used mice to study this further, focusing on how FGF12 affects cells in the aorta. The study involved experiments with mice and human cells to see how reducing FGF12 impacts aortic health. They discovered that lowering FGF12 levels in mice reduced the severity of aortic problems and improved cell function. This suggests that FGF12 plays a significant role in the development of aortic issues in Marfan syndrome. Researchers conclude that targeting FGF12 could be a promising way to treat or prevent these problems in people with Marfan syndrome. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"FGF12 induces aberrant mechanosignaling in aortic smooth muscle cells during thoracic aortic aneurysm formation in Marfan syndrome mice","authors":"Koung Li Kim, Minju Kim, Yubin Hwang, Duk-Kyung Kim, Jeongmin Kim, June Hyeok Lee, Yong-Wook Son, Jae-Hyung Jang, Kyung-Sun Heo, Misato Iwashita, Yoichi Kosodo, Wonhee Suh","doi":"10.1038/s12276-025-01621-y","DOIUrl":"10.1038/s12276-025-01621-y","url":null,"abstract":"Marfan syndrome (MFS), caused by mutations in the FBN1 gene, predisposes individuals to thoracic aortic aneurysm (TAA), a life-threatening complication. Recent studies have suggested that dysregulated mechanosignaling in aortic smooth muscle cells (SMCs) plays a pivotal role in TAA pathogenesis in MFS. However, the key molecular drivers remain largely undefined. Here we identify fibroblast growth factor 12 (FGF12) as a novel mediator of aberrant mechanosignaling in aortic SMCs during TAA formation in MFS. FGF12 is markedly upregulated in aortic SMCs of thoracic aneurysmal aortas from Fbn1C1039G/+ MFS mice and from patients with MFS. Mechanistically, FGF12 expression is induced by transforming growth factor-β/SMAD signaling and by cyclic mechanical stretch in aortic SMCs. FGF12 upregulates the expression of angiotensin II (AngII) and AngII type 1 receptor (AT1R), thereby activating the AngII/AT1R signaling pathway. FGF12-induced AT1R activation promotes aberrant mechanosignaling, as indicated by increased RhoA-GTP levels, stress fiber formation, focal adhesion assembly and focal adhesion kinase phosphorylation, ultimately leading to increased aortic SMC stiffness. In vivo studies using Fgf12 heterozygous (Fgf12+/−) mice reveal that Fgf12 haploinsufficiency significantly ameliorates AngII/β-aminopropionitrile-induced TAA formation, accompanied by reduced AT1R signaling and attenuation of aberrant mechanosignaling in the thoracic aortas. Furthermore, in Fbn1C1039G/+ MFS mice, Fgf12 haploinsufficiency (Fgf12+/−Fbn1C1039G/+) substantially mitigates TAA progression and arterial stiffening, while alleviating dysregulated mechanosignaling in thoracic aortic SMCs. Collectively, these findings identify FGF12 as a critical regulator of aberrant mechanosignaling in aortic SMCs and a key contributor to TAA formation in MFS. Marfan syndrome is a genetic disorder affecting connective tissue, often leading to dangerous aortic problems. This study explores how a protein called FGF12 might contribute to these issues. Researchers found that FGF12 is more active in the aortas of people with Marfan syndrome, which could worsen aortic problems. They used mice to study this further, focusing on how FGF12 affects cells in the aorta. The study involved experiments with mice and human cells to see how reducing FGF12 impacts aortic health. They discovered that lowering FGF12 levels in mice reduced the severity of aortic problems and improved cell function. This suggests that FGF12 plays a significant role in the development of aortic issues in Marfan syndrome. Researchers conclude that targeting FGF12 could be a promising way to treat or prevent these problems in people with Marfan syndrome. 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":"58 1","pages":"199-210"},"PeriodicalIF":12.9,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01621-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145991594","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 : 2026-01-15DOI: 10.1038/s12276-025-01618-7
Rong Li, Jing Zhang, Qiong Wang, Jun-Qi Fan, Bin Lin
Selective neuronal vulnerability is a common feature of neurodegenerative disorders. However, the molecular mechanisms that drive this selective vulnerability are not fully understood. Here we observed that microglial CX3CR1 interference induced proinflammatory responses in microglia and astrocytes that were correlated with the selective vulnerability of cone photoreceptors in the mouse retina. Via proteomic analysis, we identified STAT3 as a potential downstream target by which CX3CR1 mediates microglial neurotoxicity. Moreover, single-cell RNA sequencing analysis revealed that CX3CR1-deficient microglia exhibit eight distinct transcriptomic phenotypes. At the mechanistic level, our data revealed that the involvement of Tnf-dominant microglia occurred mainly via microglia‒cone interactions through CCLs and their receptor, atypical chemokine receptor 1 (Ackr1), whose expression was upregulated primarily in cones through NF-κB signaling, leading to selective cone loss. In addition, we found that Cxcl1-dominant microglia primarily communicated with astrocytes via the Bmp2–Bmpr1a/Bmpr1b pair, leading to increased STAT3 levels and, consequently, elevated CCL and CXCL production in astrocytes, which in turn contributed to further cone loss through Ackr1. Overall, our data demonstrate that microglial CX3CR1 deficiency induces selective cone cell death via activation of the STAT3/CCL–ACKR1 signaling pathway, and that targeting CX3CR1/STAT3 could represent a therapeutic strategy to reduce microglial neurotoxicity. This study explores why certain neurons in the brain are more vulnerable in degenerative contexts such as Alzheimer’s disease. The study investigates the role of CX3CL1/CX3CR1 signaling in selective neuronal vulnerability in the retina, an extension of the brain. They found that CX3CR1 deficiency in microglia activates STAT3 signaling, triggering proinflammatory responses in both microglia and astrocytes. This neuroinflammation, mediated by chemokines such as CCL and CXCL, specifically targets cone photoreceptors primarily expressing Ackr1, leading to their selective vulnerability and loss. These findings demonstrate that the CX3CR1/STAT3 pathway is a key mechanism driving selective neuronal damage, suggesting it as a promising therapeutic target for mitigating microglia-mediated neurotoxicity in neurological disorders. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Microglial CX3CR1 deficiency regulates the selective vulnerability of cone photoreceptors via STAT3/CCL–ACKR1 signaling in the mouse retina","authors":"Rong Li, Jing Zhang, Qiong Wang, Jun-Qi Fan, Bin Lin","doi":"10.1038/s12276-025-01618-7","DOIUrl":"10.1038/s12276-025-01618-7","url":null,"abstract":"Selective neuronal vulnerability is a common feature of neurodegenerative disorders. However, the molecular mechanisms that drive this selective vulnerability are not fully understood. Here we observed that microglial CX3CR1 interference induced proinflammatory responses in microglia and astrocytes that were correlated with the selective vulnerability of cone photoreceptors in the mouse retina. Via proteomic analysis, we identified STAT3 as a potential downstream target by which CX3CR1 mediates microglial neurotoxicity. Moreover, single-cell RNA sequencing analysis revealed that CX3CR1-deficient microglia exhibit eight distinct transcriptomic phenotypes. At the mechanistic level, our data revealed that the involvement of Tnf-dominant microglia occurred mainly via microglia‒cone interactions through CCLs and their receptor, atypical chemokine receptor 1 (Ackr1), whose expression was upregulated primarily in cones through NF-κB signaling, leading to selective cone loss. In addition, we found that Cxcl1-dominant microglia primarily communicated with astrocytes via the Bmp2–Bmpr1a/Bmpr1b pair, leading to increased STAT3 levels and, consequently, elevated CCL and CXCL production in astrocytes, which in turn contributed to further cone loss through Ackr1. Overall, our data demonstrate that microglial CX3CR1 deficiency induces selective cone cell death via activation of the STAT3/CCL–ACKR1 signaling pathway, and that targeting CX3CR1/STAT3 could represent a therapeutic strategy to reduce microglial neurotoxicity. This study explores why certain neurons in the brain are more vulnerable in degenerative contexts such as Alzheimer’s disease. The study investigates the role of CX3CL1/CX3CR1 signaling in selective neuronal vulnerability in the retina, an extension of the brain. They found that CX3CR1 deficiency in microglia activates STAT3 signaling, triggering proinflammatory responses in both microglia and astrocytes. This neuroinflammation, mediated by chemokines such as CCL and CXCL, specifically targets cone photoreceptors primarily expressing Ackr1, leading to their selective vulnerability and loss. These findings demonstrate that the CX3CR1/STAT3 pathway is a key mechanism driving selective neuronal damage, suggesting it as a promising therapeutic target for mitigating microglia-mediated neurotoxicity in neurological disorders. 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":"58 1","pages":"178-198"},"PeriodicalIF":12.9,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01618-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971518","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 : 2026-01-15DOI: 10.1038/s12276-025-01623-w
Weili Denyse Chang, Young-Jun Choe
Aberrant mRNAs can arise from errors in RNA processing or from various physicochemical insults. Ribosomes translating such faulty mRNAs may stall, producing incomplete and potentially toxic polypeptides. These aberrant translation products are eliminated by the ribosome-associated quality control pathway. Ribosome stalling also leads to ribosome collisions, which can activate signaling pathways that enable cells to adapt to stress or determine cell fate. Here, in this Review, we summarize the molecular mechanisms of ribosome stalling and the associated quality control and signaling pathways, and discuss their implications in disease and therapeutics. Proteins sometimes fold incorrectly, which can cause problems in cells. This Review explores how ribosomes can stall and lead to protein misfolding. The researchers review how ribosome stalling happens and how cells respond, focusing on a process called ribosome-associated quality control (RQC). RQC helps degrade faulty proteins and is crucial for maintaining cell health. The study explains that ribosome stalling can occur due to damaged RNA or specific sequences in the genetic code. Cells have mechanisms to resolve these stalls, such as splitting the ribosome into parts and degrading the faulty protein. Research highlights that defects in these processes are linked to aging and diseases such as neurodegeneration. The researchers conclude that understanding RQC better could lead to new treatments for diseases caused by protein misfolding. Future research may uncover more about how cells manage protein production and maintain health. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Quality control and signaling pathways at stalled ribosomes","authors":"Weili Denyse Chang, Young-Jun Choe","doi":"10.1038/s12276-025-01623-w","DOIUrl":"10.1038/s12276-025-01623-w","url":null,"abstract":"Aberrant mRNAs can arise from errors in RNA processing or from various physicochemical insults. Ribosomes translating such faulty mRNAs may stall, producing incomplete and potentially toxic polypeptides. These aberrant translation products are eliminated by the ribosome-associated quality control pathway. Ribosome stalling also leads to ribosome collisions, which can activate signaling pathways that enable cells to adapt to stress or determine cell fate. Here, in this Review, we summarize the molecular mechanisms of ribosome stalling and the associated quality control and signaling pathways, and discuss their implications in disease and therapeutics. Proteins sometimes fold incorrectly, which can cause problems in cells. This Review explores how ribosomes can stall and lead to protein misfolding. The researchers review how ribosome stalling happens and how cells respond, focusing on a process called ribosome-associated quality control (RQC). RQC helps degrade faulty proteins and is crucial for maintaining cell health. The study explains that ribosome stalling can occur due to damaged RNA or specific sequences in the genetic code. Cells have mechanisms to resolve these stalls, such as splitting the ribosome into parts and degrading the faulty protein. Research highlights that defects in these processes are linked to aging and diseases such as neurodegeneration. The researchers conclude that understanding RQC better could lead to new treatments for diseases caused by protein misfolding. Future research may uncover more about how cells manage protein production and maintain health. 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":"58 1","pages":"82-93"},"PeriodicalIF":12.9,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01623-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971534","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 : 2026-01-14DOI: 10.1038/s12276-025-01612-z
Yong Tang, Jiulin Tan, Qixiu Yu, Wenxin Yang, Zhengrong Chen, Yueqi Chen, Qiankun Yang, Jie Zhang, Qijie Dai, Bo Yu, Yunqin Xu, Linying Zhou, Gang Wang, Ce Dou, Junping Wang, Fei Luo
It has been reported that a close relationship exists between the hematopoietic and skeletal systems, and megakaryocytes (MKs) may play a role in maintaining bone homeostasis. However, the precise role and underlying mechanisms of MKs in osteogenesis, particularly under stress conditions, remain largely unknown. Here we demonstrate that deficiency of MKs significantly impairs bone formation, accompanied by a reduction in the number of leptin receptor positive skeletal stem cells (LepR+ SSCs) in MKs conditionally deleted mice. Further investigations reveal that megakaryocytic TGFβ1 promotes the osteogenic differentiation of LepR+ SSCs following irradiation. Notably, thrombopoietin treatment effectively maintains the number of LepR+ SSCs and stimulates bone formation. Moreover, MKs-derived TGFβ1 facilitates zinc ions influx into LepR+ SSCs by activating Slc39a14, thereby alleviating endoplasmic reticulum stress after irradiation. In addition, the increased intracellular zinc levels inhibit PTP1B expression and activate Stat3 signaling, promoting osteogenic lineage commitment. In conclusion, our findings demonstrate that the megakaryocytic TGFβ1 orchestrates the osteogenesis of LepR+ SSCs following irradiation, offering a potential therapeutic strategy for radiation-induced bone loss. This study explores how certain cells in our bones, called skeletal stem cells (SSCs), help maintain bone health and repair damage. The researchers found that a small group of cells, known as leptin receptor-positive (LepR+) SSCs, are crucial for bone repair. The study focused on how megakaryocytes (MKs), a type of bone marrow cell, support these SSCs. The researchers used mice to study the effects of radiation on bones and how MKs help LepR+ SSCs recover. They discovered that MKs release a protein called TGFβ1, which helps LepR+ SSCs absorb zinc ions. This process reduces stress in the cells and encourages them to become osteoblasts. The study also showed that increasing MKs in the bone marrow can improve bone strength after radiation. In conclusion, MKs play a vital role in bone repair by supporting LepR+ SSCs. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Megakaryocytic TGFβ1 orchestrates osteogenesis of LepR+ SSCs to alleviate radiation-induced bone loss","authors":"Yong Tang, Jiulin Tan, Qixiu Yu, Wenxin Yang, Zhengrong Chen, Yueqi Chen, Qiankun Yang, Jie Zhang, Qijie Dai, Bo Yu, Yunqin Xu, Linying Zhou, Gang Wang, Ce Dou, Junping Wang, Fei Luo","doi":"10.1038/s12276-025-01612-z","DOIUrl":"10.1038/s12276-025-01612-z","url":null,"abstract":"It has been reported that a close relationship exists between the hematopoietic and skeletal systems, and megakaryocytes (MKs) may play a role in maintaining bone homeostasis. However, the precise role and underlying mechanisms of MKs in osteogenesis, particularly under stress conditions, remain largely unknown. Here we demonstrate that deficiency of MKs significantly impairs bone formation, accompanied by a reduction in the number of leptin receptor positive skeletal stem cells (LepR+ SSCs) in MKs conditionally deleted mice. Further investigations reveal that megakaryocytic TGFβ1 promotes the osteogenic differentiation of LepR+ SSCs following irradiation. Notably, thrombopoietin treatment effectively maintains the number of LepR+ SSCs and stimulates bone formation. Moreover, MKs-derived TGFβ1 facilitates zinc ions influx into LepR+ SSCs by activating Slc39a14, thereby alleviating endoplasmic reticulum stress after irradiation. In addition, the increased intracellular zinc levels inhibit PTP1B expression and activate Stat3 signaling, promoting osteogenic lineage commitment. In conclusion, our findings demonstrate that the megakaryocytic TGFβ1 orchestrates the osteogenesis of LepR+ SSCs following irradiation, offering a potential therapeutic strategy for radiation-induced bone loss. This study explores how certain cells in our bones, called skeletal stem cells (SSCs), help maintain bone health and repair damage. The researchers found that a small group of cells, known as leptin receptor-positive (LepR+) SSCs, are crucial for bone repair. The study focused on how megakaryocytes (MKs), a type of bone marrow cell, support these SSCs. The researchers used mice to study the effects of radiation on bones and how MKs help LepR+ SSCs recover. They discovered that MKs release a protein called TGFβ1, which helps LepR+ SSCs absorb zinc ions. This process reduces stress in the cells and encourages them to become osteoblasts. The study also showed that increasing MKs in the bone marrow can improve bone strength after radiation. In conclusion, MKs play a vital role in bone repair by supporting LepR+ SSCs. 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":"58 1","pages":"161-177"},"PeriodicalIF":12.9,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01612-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971407","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 : 2026-01-14DOI: 10.1038/s12276-026-01638-x
Seung-Hyun Bae, Jung-Hoon Kim, Tae Hyun Park, Kyeong Lee, Byung Il Lee, Hyonchol Jang
{"title":"Author Correction: BMS794833 inhibits macrophage efferocytosis by directly binding to MERTK and inhibiting its activity","authors":"Seung-Hyun Bae, Jung-Hoon Kim, Tae Hyun Park, Kyeong Lee, Byung Il Lee, Hyonchol Jang","doi":"10.1038/s12276-026-01638-x","DOIUrl":"10.1038/s12276-026-01638-x","url":null,"abstract":"","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"58 1","pages":"300-300"},"PeriodicalIF":12.9,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-026-01638-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145985737","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 : 2026-01-14DOI: 10.1038/s12276-025-01622-x
Jina Kim, Ju Dong Yang, Vatche G. Agopian, Yazhen Zhu, Hsian-Rong Tseng, Sungyong You
Extracellular vesicles (EVs) are emerging as promising noninvasive biomarkers, yet their clinical translation faces substantial hurdles, primarily due to the challenge of identifying assay-compatible markers. Here, in this Review, we outline sophisticated computational frameworks, particularly leveraging artificial intelligence, to bridge this gap. We detail the integration of diverse data resources, including disease-specific omics, EV, protein localization, tissue-specific, drug, model system and immune databases. This Review comprehensively describes computational selection strategies, from rule-based sequential filtering to advanced machine learning for data fusion and deep learning for multi-omics integration. Crucially, it discusses the refinement of biomarker candidates using artificial-intelligence-driven predictions of protein structure and physicochemical properties, ensuring compatibility with existing assay systems. By systematically evaluating biomarkers for predictive performance, biological plausibility and clinical utility, this framework aims to accelerate the transition of EV research from discovery to clinical application, thereby enhancing precision medicine. Extracellular vesicles (EVs) are nanosized particles released by cells, carrying RNA, proteins and lipids. They hold promise as noninvasive markers for diseases such as cancer and neurodegenerative disorders. However, using EVs in clinical settings is challenging. Many candidate markers identified in research do not work well with current testing methods. In 2021 alone, over 1,000 studies on EV markers were published, but only 4 were clinically validated. This Review emphasizes the need for advanced computational tools to identify clinically viable markers. The authors discuss various data resources and computational strategies, including artificial intelligence approaches that predict protein structures, interactions and assay compatibility to prioritize candidates. The study concludes that combining advanced computational approaches with EV assays can speed up the transition from research to clinical practice. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Computational frameworks for enhanced extracellular vesicle biomarker discovery","authors":"Jina Kim, Ju Dong Yang, Vatche G. Agopian, Yazhen Zhu, Hsian-Rong Tseng, Sungyong You","doi":"10.1038/s12276-025-01622-x","DOIUrl":"10.1038/s12276-025-01622-x","url":null,"abstract":"Extracellular vesicles (EVs) are emerging as promising noninvasive biomarkers, yet their clinical translation faces substantial hurdles, primarily due to the challenge of identifying assay-compatible markers. Here, in this Review, we outline sophisticated computational frameworks, particularly leveraging artificial intelligence, to bridge this gap. We detail the integration of diverse data resources, including disease-specific omics, EV, protein localization, tissue-specific, drug, model system and immune databases. This Review comprehensively describes computational selection strategies, from rule-based sequential filtering to advanced machine learning for data fusion and deep learning for multi-omics integration. Crucially, it discusses the refinement of biomarker candidates using artificial-intelligence-driven predictions of protein structure and physicochemical properties, ensuring compatibility with existing assay systems. By systematically evaluating biomarkers for predictive performance, biological plausibility and clinical utility, this framework aims to accelerate the transition of EV research from discovery to clinical application, thereby enhancing precision medicine. Extracellular vesicles (EVs) are nanosized particles released by cells, carrying RNA, proteins and lipids. They hold promise as noninvasive markers for diseases such as cancer and neurodegenerative disorders. However, using EVs in clinical settings is challenging. Many candidate markers identified in research do not work well with current testing methods. In 2021 alone, over 1,000 studies on EV markers were published, but only 4 were clinically validated. This Review emphasizes the need for advanced computational tools to identify clinically viable markers. The authors discuss various data resources and computational strategies, including artificial intelligence approaches that predict protein structures, interactions and assay compatibility to prioritize candidates. The study concludes that combining advanced computational approaches with EV assays can speed up the transition from research to clinical practice. 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":"58 1","pages":"73-81"},"PeriodicalIF":12.9,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01622-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971469","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 : 2026-01-09DOI: 10.1038/s12276-025-01616-9
Fan-feng Chen, Yin-he Zhang, Zi-chang Wu, Kaiyi Du, Xinyuan Chen, Yang Lu, Qianqian Hu, Anyu Du, Shenghu Du, Jian Wang, Keqing Shi, Zimiao Chen, Zili He, Kailiang Zhou, Jian Xiao
Acute limb ischemia–reperfusion injury (ALIRI) prominently involves microvascular dysfunction, with notable contributions from damage to microvascular endothelial cells (MECs). Previous research suggests that the mechanosensitive ion channel Piezo1 becomes active in response to mechanical stress conditions, including ischemia and trauma. However, its precise function within the ALIRI context remains elusive. Notably, the expression of Piezo1 was markedly elevated postreperfusion in mouse hind limb ischemia/reperfusion (I/R) models, implicating its crucial involvement in limb survival. Employing specific inhibitors of cell death pathways, the study delineated key molecular drivers of ferroptosis during limb damage. Here evaluations of limb vitality, western blot, quantitative PCR and immunofluorescence implicated that activation of Piezo1 by its agonist exacerbates I/R-induced microvascular perfusion deficits, tissue swelling, skeletal muscle damage and increased tissue infarction and MECs damage. Conversely, these detrimental impacts were mitigated through pharmacological blockade of Piezo1 or specific deletion of Piezo1 in MECs. Comprehensive untargeted metabolomic analysis revealed significant changes primarily in glycerophospholipid and arachidonic acid metabolism pathways. Further experiments demonstrated that RNA interference-mediated inhibition of cytosolic phospholipase A2 (cPLA2) and acyl-CoA synthetase long-chain family member 4 (ACSL4) negated the protective effects against ferroptosis and limb damage that were observed with Piezo1 deletion. Moreover, this study confirmed that protein kinase C phosphorylates ACSL4, which mediates Piezo1-induced ferroptosis and exacerbates limb damage, as shown through immunoprecipitation studies. In summary, Piezo1 contributes to the exacerbation of microvascular and skeletal muscle damage in ALIRI by facilitating the cPLA2-dependent release of arachidonic acid and promoting ACSL4-driven lipid peroxidation, thereby intensifying ferroptosis in MECs. Acute limb ischemia–reperfusion injury (ALIRI) is a serious condition that can occur after blood flow is restored to a limb. This can cause damage to small blood vessels and tissues. Here researchers wanted to understand how a protein called Piezo1 affects this process. The researchers created a model of ALIRI in mice and observed the effects of Piezo1 on cell death and tissue damage. They found that Piezo1 activation increases calcium levels in cells, which then triggers a series of reactions leading to cell death through a process called ferroptosis. They also discovered that inhibiting Piezo1 reduced tissue damage and cell death. The study concludes that targeting Piezo1 could be a potential strategy to prevent tissue damage in ALIRI. Future research may focus on developing treatments that inhibit Piezo1 to improve outcomes for patients with this condition. This summary was initially drafted using artificial intelligence, then revised and fact-checked by t
{"title":"Piezo1 activation in endothelial cells aggravates microvascular ischemia–reperfusion injury in limbs by enhancing ferroptosis","authors":"Fan-feng Chen, Yin-he Zhang, Zi-chang Wu, Kaiyi Du, Xinyuan Chen, Yang Lu, Qianqian Hu, Anyu Du, Shenghu Du, Jian Wang, Keqing Shi, Zimiao Chen, Zili He, Kailiang Zhou, Jian Xiao","doi":"10.1038/s12276-025-01616-9","DOIUrl":"10.1038/s12276-025-01616-9","url":null,"abstract":"Acute limb ischemia–reperfusion injury (ALIRI) prominently involves microvascular dysfunction, with notable contributions from damage to microvascular endothelial cells (MECs). Previous research suggests that the mechanosensitive ion channel Piezo1 becomes active in response to mechanical stress conditions, including ischemia and trauma. However, its precise function within the ALIRI context remains elusive. Notably, the expression of Piezo1 was markedly elevated postreperfusion in mouse hind limb ischemia/reperfusion (I/R) models, implicating its crucial involvement in limb survival. Employing specific inhibitors of cell death pathways, the study delineated key molecular drivers of ferroptosis during limb damage. Here evaluations of limb vitality, western blot, quantitative PCR and immunofluorescence implicated that activation of Piezo1 by its agonist exacerbates I/R-induced microvascular perfusion deficits, tissue swelling, skeletal muscle damage and increased tissue infarction and MECs damage. Conversely, these detrimental impacts were mitigated through pharmacological blockade of Piezo1 or specific deletion of Piezo1 in MECs. Comprehensive untargeted metabolomic analysis revealed significant changes primarily in glycerophospholipid and arachidonic acid metabolism pathways. Further experiments demonstrated that RNA interference-mediated inhibition of cytosolic phospholipase A2 (cPLA2) and acyl-CoA synthetase long-chain family member 4 (ACSL4) negated the protective effects against ferroptosis and limb damage that were observed with Piezo1 deletion. Moreover, this study confirmed that protein kinase C phosphorylates ACSL4, which mediates Piezo1-induced ferroptosis and exacerbates limb damage, as shown through immunoprecipitation studies. In summary, Piezo1 contributes to the exacerbation of microvascular and skeletal muscle damage in ALIRI by facilitating the cPLA2-dependent release of arachidonic acid and promoting ACSL4-driven lipid peroxidation, thereby intensifying ferroptosis in MECs. Acute limb ischemia–reperfusion injury (ALIRI) is a serious condition that can occur after blood flow is restored to a limb. This can cause damage to small blood vessels and tissues. Here researchers wanted to understand how a protein called Piezo1 affects this process. The researchers created a model of ALIRI in mice and observed the effects of Piezo1 on cell death and tissue damage. They found that Piezo1 activation increases calcium levels in cells, which then triggers a series of reactions leading to cell death through a process called ferroptosis. They also discovered that inhibiting Piezo1 reduced tissue damage and cell death. The study concludes that targeting Piezo1 could be a potential strategy to prevent tissue damage in ALIRI. Future research may focus on developing treatments that inhibit Piezo1 to improve outcomes for patients with this condition. This summary was initially drafted using artificial intelligence, then revised and fact-checked by t","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"58 1","pages":"143-160"},"PeriodicalIF":12.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01616-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145935975","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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