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}
Pub Date : 2026-01-09DOI: 10.1038/s12276-025-01613-y
Sungjoon Oh, Seokjae Park, Eun-Kyoung Kim
Intermittent fasting (IF) is a safe and sustainable approach for obesity treatment, yet its weight loss efficacy is relatively modest compared with that of pharmacologic anti-obesity therapies. The synergistic benefits of pairing IF with administration of nutrient-derived metabolites remain poorly understood. Here we report that combining IF with threonic acid (TA), an ascorbic acid metabolite, led to more pronounced reductions in body weight and food intake, as well as improvements in energy expenditure and glycemic control, compared with either intervention alone in diet-induced obese mice. These metabolic benefits were associated with the anorexigenic role of TA in reversing fasting-induced upregulation of the hypothalamic orexigenic neuropeptides NPY and AGRP. In the hypothalamus, TA competed with glucose for uptake via glucose transporter 3 (GLUT3), while IF boosted the TA uptake through both glucose depletion and upregulation of GLUT3, resulting in a more robust suppression of NPY and AGRP expression. Collectively, our findings highlight the combination of TA with IF as a promising metabolite-based combinatorial strategy to enhance the therapeutic efficacy of obesity treatment. Obesity is a growing health issue worldwide. Current treatments have side effects and limited long-term success. This study explores combining intermittent fasting (IF), a dietary approach involving alternating periods of eating and fasting, with either ascorbic acid (AA, also known as vitamin C) or its metabolite, threonic acid (TA), to enhance obesity treatment. In the study, mice were fed a high-fat diet to induce obesity and then subjected to IF and AA or TA treatments. Researchers found that IF combined with TA was more effective than IF with AA or either treatment alone in reducing body weight and improving metabolic health. These metabolic benefits were associated with TA’s appetite-suppressing action in reversing fasting-induced increases in hypothalamic orexigenic neuropeptides. The study concludes that TA could be a promising strategy for treating obesity. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Threonic acid, an ascorbic acid metabolite, synergizes with intermittent fasting to ameliorate obesity","authors":"Sungjoon Oh, Seokjae Park, Eun-Kyoung Kim","doi":"10.1038/s12276-025-01613-y","DOIUrl":"10.1038/s12276-025-01613-y","url":null,"abstract":"Intermittent fasting (IF) is a safe and sustainable approach for obesity treatment, yet its weight loss efficacy is relatively modest compared with that of pharmacologic anti-obesity therapies. The synergistic benefits of pairing IF with administration of nutrient-derived metabolites remain poorly understood. Here we report that combining IF with threonic acid (TA), an ascorbic acid metabolite, led to more pronounced reductions in body weight and food intake, as well as improvements in energy expenditure and glycemic control, compared with either intervention alone in diet-induced obese mice. These metabolic benefits were associated with the anorexigenic role of TA in reversing fasting-induced upregulation of the hypothalamic orexigenic neuropeptides NPY and AGRP. In the hypothalamus, TA competed with glucose for uptake via glucose transporter 3 (GLUT3), while IF boosted the TA uptake through both glucose depletion and upregulation of GLUT3, resulting in a more robust suppression of NPY and AGRP expression. Collectively, our findings highlight the combination of TA with IF as a promising metabolite-based combinatorial strategy to enhance the therapeutic efficacy of obesity treatment. Obesity is a growing health issue worldwide. Current treatments have side effects and limited long-term success. This study explores combining intermittent fasting (IF), a dietary approach involving alternating periods of eating and fasting, with either ascorbic acid (AA, also known as vitamin C) or its metabolite, threonic acid (TA), to enhance obesity treatment. In the study, mice were fed a high-fat diet to induce obesity and then subjected to IF and AA or TA treatments. Researchers found that IF combined with TA was more effective than IF with AA or either treatment alone in reducing body weight and improving metabolic health. These metabolic benefits were associated with TA’s appetite-suppressing action in reversing fasting-induced increases in hypothalamic orexigenic neuropeptides. The study concludes that TA could be a promising strategy for treating obesity. 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":"126-142"},"PeriodicalIF":12.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01613-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145936046","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 : 2026-01-08DOI: 10.1038/s12276-025-01614-x
Laura Shih Hui Goh, Dexter Kai Hao Thng, Yvonne Li En Ang, Dean Ho, Tan Boon Toh, Andrea Li Ann Wong
Precision oncology has emerged as a promising strategy for treating high-grade gliomas, yet its clinical impact has been disappointing, with over 300 clinical trials on targeted therapies failing to yield substantial improvements in patient outcomes. Current approaches primarily focus on static, marker-driven tumor features, which capture only a small portion of the complex biology that governs therapeutic responses. Functional precision oncology (FPO) offers a complementary approach, enhancing treatment selection in a personalized manner by dynamically testing patient-derived tumor cells against a range of available therapeutic agents. Here this review examines both historical and contemporary treatment strategies for high-grade gliomas and explores underlying reasons for the limited success of multiple precision oncology initiatives. We demonstrate how the incorporation of FPO in the armamentarium of glioma therapies may address these challenges and outline its proposed role as well as the practical considerations in utilizing FPO for clinical decision-making in patients with glioma. Precision oncology aims to tailor cancer treatments based on individual genetic profiles. This study highlights the challenges faced in using genomic data alone to predict treatment outcomes for high-grade gliomas. The researchers discuss the emergence of functional precision oncology (FPO) as a promising strategy. FPO involves testing a patient’s tumor cells directly against various drugs to identify effective treatments. This method considers the complex biology of tumors, which genomic data alone may not capture. In their study, the authors addresses the use of patient-derived models, such as organoids (3D cell cultures), to test drug responses. These models help identify personalized treatment options by simulating how tumors react to different therapies. The study concludes that FPO can complement genomic approaches, offering a more comprehensive understanding of tumor behavior and improving treatment strategies for high-grade gliomas. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"The functional imperative in high-grade glioma","authors":"Laura Shih Hui Goh, Dexter Kai Hao Thng, Yvonne Li En Ang, Dean Ho, Tan Boon Toh, Andrea Li Ann Wong","doi":"10.1038/s12276-025-01614-x","DOIUrl":"10.1038/s12276-025-01614-x","url":null,"abstract":"Precision oncology has emerged as a promising strategy for treating high-grade gliomas, yet its clinical impact has been disappointing, with over 300 clinical trials on targeted therapies failing to yield substantial improvements in patient outcomes. Current approaches primarily focus on static, marker-driven tumor features, which capture only a small portion of the complex biology that governs therapeutic responses. Functional precision oncology (FPO) offers a complementary approach, enhancing treatment selection in a personalized manner by dynamically testing patient-derived tumor cells against a range of available therapeutic agents. Here this review examines both historical and contemporary treatment strategies for high-grade gliomas and explores underlying reasons for the limited success of multiple precision oncology initiatives. We demonstrate how the incorporation of FPO in the armamentarium of glioma therapies may address these challenges and outline its proposed role as well as the practical considerations in utilizing FPO for clinical decision-making in patients with glioma. Precision oncology aims to tailor cancer treatments based on individual genetic profiles. This study highlights the challenges faced in using genomic data alone to predict treatment outcomes for high-grade gliomas. The researchers discuss the emergence of functional precision oncology (FPO) as a promising strategy. FPO involves testing a patient’s tumor cells directly against various drugs to identify effective treatments. This method considers the complex biology of tumors, which genomic data alone may not capture. In their study, the authors addresses the use of patient-derived models, such as organoids (3D cell cultures), to test drug responses. These models help identify personalized treatment options by simulating how tumors react to different therapies. The study concludes that FPO can complement genomic approaches, offering a more comprehensive understanding of tumor behavior and improving treatment strategies for high-grade gliomas. 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":"43-58"},"PeriodicalIF":12.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01614-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918959","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}
Accumulating evidence has revealed noncoding RNAs (ncRNAs) as versatile regulators in skeletal muscle development, extending beyond their canonical roles as nontranslating transcripts. Recent advancements in proteomics and translatomics have demonstrated that ncRNAs containing cryptic open reading frames can encode peptides/proteins. Here we systematically evaluate computational tools and databases for predicting ncRNA-encoded products, dissect the molecular mechanisms underlying their translation and synthesize the current landscape of ncRNA-derived peptides/proteins identified in skeletal muscle across species. We further discuss their emerging roles in myogenesis and potential clinical implications for muscle-related disorders. By highlighting the dual functionality of ncRNAs as both regulatory RNAs and peptide/protein precursors, this work provides a comprehensive resource for understanding the expanding complexity of skeletal muscle development and proposes novel therapeutic targets for muscle diseases. The study explores the role of noncoding RNAs (ncRNAs) in muscle development and disease. Here, we address the gap in understanding how these ncRNA-encoded peptides function in muscle biology. Researchers reviewed methods to predict and validate the protein-coding potential of ncRNAs. They used bioinformatics tools to identify small open reading frames within ncRNAs, which are sequences that can potentially code for proteins. Techniques such as ribosome profiling (Ribo-seq) and mass spectrometry were employed to confirm the presence of these peptides. The findings reveal that ncRNA-encoded peptides play crucial roles in muscle development and may offer new therapeutic targets for muscle diseases. For instance, some peptides regulate calcium transport in muscle cells, affecting contraction and growth. The study concludes that understanding ncRNA-encoded peptides could lead to novel treatments for muscle disorders. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Revisiting noncoding RNAs: emerging coding functions and their impact on skeletal muscle development","authors":"Dandan Zhong, Jian Wang, Qi Li, Chuang Wang, Yuanyuan Huang, Yanhong Cao, Hui Li","doi":"10.1038/s12276-025-01610-1","DOIUrl":"10.1038/s12276-025-01610-1","url":null,"abstract":"Accumulating evidence has revealed noncoding RNAs (ncRNAs) as versatile regulators in skeletal muscle development, extending beyond their canonical roles as nontranslating transcripts. Recent advancements in proteomics and translatomics have demonstrated that ncRNAs containing cryptic open reading frames can encode peptides/proteins. Here we systematically evaluate computational tools and databases for predicting ncRNA-encoded products, dissect the molecular mechanisms underlying their translation and synthesize the current landscape of ncRNA-derived peptides/proteins identified in skeletal muscle across species. We further discuss their emerging roles in myogenesis and potential clinical implications for muscle-related disorders. By highlighting the dual functionality of ncRNAs as both regulatory RNAs and peptide/protein precursors, this work provides a comprehensive resource for understanding the expanding complexity of skeletal muscle development and proposes novel therapeutic targets for muscle diseases. The study explores the role of noncoding RNAs (ncRNAs) in muscle development and disease. Here, we address the gap in understanding how these ncRNA-encoded peptides function in muscle biology. Researchers reviewed methods to predict and validate the protein-coding potential of ncRNAs. They used bioinformatics tools to identify small open reading frames within ncRNAs, which are sequences that can potentially code for proteins. Techniques such as ribosome profiling (Ribo-seq) and mass spectrometry were employed to confirm the presence of these peptides. The findings reveal that ncRNA-encoded peptides play crucial roles in muscle development and may offer new therapeutic targets for muscle diseases. For instance, some peptides regulate calcium transport in muscle cells, affecting contraction and growth. The study concludes that understanding ncRNA-encoded peptides could lead to novel treatments for muscle 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":"32-42"},"PeriodicalIF":12.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01610-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918987","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 : 2026-01-08DOI: 10.1038/s12276-025-01615-w
Yena Cho, Yong Kee Kim
Structural proteins such as actin and tubulin form the fundamental framework of the cytoskeleton and are essential for diverse cellular processes, including morphogenesis, intracellular transport and cell division. Maintaining precise intracellular levels is crucial for cellular homeostasis because both excess and deficiency can lead to cytotoxicity. Although transcriptional regulation establishes basal expression levels, recent studies have highlighted the crucial role of post-transcriptional and post-translational mechanisms in the fine-tuning of cytoskeletal protein abundance in response to dynamic cellular demands. Actin and tubulin use distinct autoregulatory strategies. Tubulin mRNA undergoes cotranslational decay, mediated by TTC5 and tightly regulated by the CARM1–PI3KC2α axis, linking ribosome-associated quality control with post-translational modifications. Conversely, actin regulation involves mRNA localization via ZBP1 and spatially restricted translation, coupled with a G-actin–MRTF/SRF transcriptional feedback loop. In addition, the ubiquitin–proteasome system modulates cytoskeletal protein turnover and fine-tunes microtubule dynamics. The dysregulation of these pathways has been implicated in various human diseases, including tubulinopathies, cancer and myopathies. In this Review, we summarize the multilayered regulatory networks that control actin and tubulin abundance, highlight recent advances in autoregulatory circuits and their disease relevance, and discuss future research directions for the therapeutic targeting of cytoskeletal proteostasis. Mammalian cells rely on structures called the cytoskeleton, which includes actin filaments and microtubules, to maintain their shape and function. This study explores how cells regulate the levels of actin and tubulin, the building blocks of these structures. When these proteins are not balanced, it can lead to cell damage. The authors review how cells control these proteins through various mechanisms. The study highlights that cells use transcriptional regulation and post-transcriptional mechanisms to manage protein levels. For example, when there is too much free tubulin, a feedback loop reduces its production by degrading its mRNA. Similarly, actin levels are controlled by feedback mechanisms that adjust mRNA stability based on the amount of unpolymerized actin. The findings emphasize the importance of these regulatory systems in maintaining cellular health. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Multilayered regulation of cytoskeletal protein abundance: autoregulatory mechanisms of actin and tubulin","authors":"Yena Cho, Yong Kee Kim","doi":"10.1038/s12276-025-01615-w","DOIUrl":"10.1038/s12276-025-01615-w","url":null,"abstract":"Structural proteins such as actin and tubulin form the fundamental framework of the cytoskeleton and are essential for diverse cellular processes, including morphogenesis, intracellular transport and cell division. Maintaining precise intracellular levels is crucial for cellular homeostasis because both excess and deficiency can lead to cytotoxicity. Although transcriptional regulation establishes basal expression levels, recent studies have highlighted the crucial role of post-transcriptional and post-translational mechanisms in the fine-tuning of cytoskeletal protein abundance in response to dynamic cellular demands. Actin and tubulin use distinct autoregulatory strategies. Tubulin mRNA undergoes cotranslational decay, mediated by TTC5 and tightly regulated by the CARM1–PI3KC2α axis, linking ribosome-associated quality control with post-translational modifications. Conversely, actin regulation involves mRNA localization via ZBP1 and spatially restricted translation, coupled with a G-actin–MRTF/SRF transcriptional feedback loop. In addition, the ubiquitin–proteasome system modulates cytoskeletal protein turnover and fine-tunes microtubule dynamics. The dysregulation of these pathways has been implicated in various human diseases, including tubulinopathies, cancer and myopathies. In this Review, we summarize the multilayered regulatory networks that control actin and tubulin abundance, highlight recent advances in autoregulatory circuits and their disease relevance, and discuss future research directions for the therapeutic targeting of cytoskeletal proteostasis. Mammalian cells rely on structures called the cytoskeleton, which includes actin filaments and microtubules, to maintain their shape and function. This study explores how cells regulate the levels of actin and tubulin, the building blocks of these structures. When these proteins are not balanced, it can lead to cell damage. The authors review how cells control these proteins through various mechanisms. The study highlights that cells use transcriptional regulation and post-transcriptional mechanisms to manage protein levels. For example, when there is too much free tubulin, a feedback loop reduces its production by degrading its mRNA. Similarly, actin levels are controlled by feedback mechanisms that adjust mRNA stability based on the amount of unpolymerized actin. The findings emphasize the importance of these regulatory systems in maintaining cellular 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":"59-72"},"PeriodicalIF":12.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01615-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919040","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 : 2026-01-07DOI: 10.1038/s12276-025-01599-7
Yeong Hak Bang, Ji Hye Choi, Kyunghee Park, Boram Lee, Kyung Yeon Han, Dae Hee Pyo, Yong Beom Cho, Tae-You Kim, Kyu Joo Park, Seung-Bum Ryoo, Sung-Bum Kang, Chang Sik Yu, Jaeim Lee, Kil-yong Lee, Kyu-Tae Kim, Jin-Young Lee, Hoang Bao Khanh Chu, Nameeta Shah, Shashank Gupta, Pranali Sonpatki, Young-Joon Kim, Woong-Yang Park
Here we aimed to evaluate the feasibility of distinguishing colorectal microenvironments that support cancer cell growth from those that do not. We hypothesized that patients whose non-tumor-bearing tissue (NBT) obtained from the furthest margins of resected cancer specimens resembled the tumor had a poorer prognosis. Patients with colorectal cancer were divided into groups with tumor-supportive (TSM) or healthy microenvironments using bulk RNA sequencing data from 273 paired NBT and tumor samples. Patients in the TSM group exhibited significantly poorer 5-year recurrence-free survival and overall survival compared with those in the healthy microenvironment group. Pathway and 16S rRNA sequencing analyses revealed that NBT and tumors from the TSM group shared a microbiome composition, along with decreased pathway activity related to microvilli maintenance and flavonoid or vitamin metabolic processes. Single-cell RNA sequencing uncovered upregulated interactions between IL1Bhigh neutrophils and OLFM4+ epithelial cells in NBTs from the TSM group, as well as organized microniches in TSM tumors, featuring interactions between EMP1high epithelial cells, IL1Bhigh neutrophils and GZMKhigh CD8+ T cells. Collectively, the colorectal microenvironment can serve as a prognostic biomarker to effectively predict cancer invasiveness and tumor-promoting inflammation. Maintaining a healthy colorectal mucosal microenvironment, potentially through dietary intervention, is crucial. Colorectal cancer (CRC) is a complex disease with varied genetic and environmental factors. Current genomic markers help to predict treatment outcomes for advanced cases but not for early-stage CRC. About 30–40% of CRC cases return after surgery, indicating a need for better predictive tools. Researchers explored using normal-looking tissue near tumors as a potential marker for recurrence. This study involved 273 patients with stage II or III CRC who underwent surgery. Researchers used RNA sequencing to analyze both the tumor and the nearby normal tissues. They identified specific genes that were more active in tumors and used these to classify patients into two groups: those with a tumor-supportive environment and those with a healthier environment. The results showed that patients with tumor-like features in their normal tissue had worse survival rates. This suggests that the surrounding tissue’s condition can predict cancer recurrence. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Colorectal microenvironment determines the prognosis of colorectal cancer","authors":"Yeong Hak Bang, Ji Hye Choi, Kyunghee Park, Boram Lee, Kyung Yeon Han, Dae Hee Pyo, Yong Beom Cho, Tae-You Kim, Kyu Joo Park, Seung-Bum Ryoo, Sung-Bum Kang, Chang Sik Yu, Jaeim Lee, Kil-yong Lee, Kyu-Tae Kim, Jin-Young Lee, Hoang Bao Khanh Chu, Nameeta Shah, Shashank Gupta, Pranali Sonpatki, Young-Joon Kim, Woong-Yang Park","doi":"10.1038/s12276-025-01599-7","DOIUrl":"10.1038/s12276-025-01599-7","url":null,"abstract":"Here we aimed to evaluate the feasibility of distinguishing colorectal microenvironments that support cancer cell growth from those that do not. We hypothesized that patients whose non-tumor-bearing tissue (NBT) obtained from the furthest margins of resected cancer specimens resembled the tumor had a poorer prognosis. Patients with colorectal cancer were divided into groups with tumor-supportive (TSM) or healthy microenvironments using bulk RNA sequencing data from 273 paired NBT and tumor samples. Patients in the TSM group exhibited significantly poorer 5-year recurrence-free survival and overall survival compared with those in the healthy microenvironment group. Pathway and 16S rRNA sequencing analyses revealed that NBT and tumors from the TSM group shared a microbiome composition, along with decreased pathway activity related to microvilli maintenance and flavonoid or vitamin metabolic processes. Single-cell RNA sequencing uncovered upregulated interactions between IL1Bhigh neutrophils and OLFM4+ epithelial cells in NBTs from the TSM group, as well as organized microniches in TSM tumors, featuring interactions between EMP1high epithelial cells, IL1Bhigh neutrophils and GZMKhigh CD8+ T cells. Collectively, the colorectal microenvironment can serve as a prognostic biomarker to effectively predict cancer invasiveness and tumor-promoting inflammation. Maintaining a healthy colorectal mucosal microenvironment, potentially through dietary intervention, is crucial. Colorectal cancer (CRC) is a complex disease with varied genetic and environmental factors. Current genomic markers help to predict treatment outcomes for advanced cases but not for early-stage CRC. About 30–40% of CRC cases return after surgery, indicating a need for better predictive tools. Researchers explored using normal-looking tissue near tumors as a potential marker for recurrence. This study involved 273 patients with stage II or III CRC who underwent surgery. Researchers used RNA sequencing to analyze both the tumor and the nearby normal tissues. They identified specific genes that were more active in tumors and used these to classify patients into two groups: those with a tumor-supportive environment and those with a healthier environment. The results showed that patients with tumor-like features in their normal tissue had worse survival rates. This suggests that the surrounding tissue’s condition can predict cancer recurrence. 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":"110-125"},"PeriodicalIF":12.9,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01599-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913486","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 : 2026-01-07DOI: 10.1038/s12276-025-01608-9
Seyeon Lim, Soyeon Woo, Ki Won Lee, Kwang Dong Kim
The cytoskeleton is a dynamic intracellular protein network composed of actin filaments, microtubules and intermediate filaments that provides structural support in cells and plays a crucial role in tumor metastasis. Tumor cells encounter various dynamic mechanical environments during metastasis, and they adapt to these environments through cytoskeletal reorganization, which enables them to regulate cell morphology, generate intracellular forces and induce intracellular signaling. Actin filaments contribute to migration and extracellular matrix degradation by forming protrusive structures, such as lamellipodia, filopodia and invadopodia. Microtubules support migration, stabilize cell polarity and enhance survival under shear stress. Intermediate filaments maintain structural integrity and mechanical flexibility, allowing cancer cells to pass through narrow spaces. The cytoskeleton’s pivotal role in regulating metastasis makes it a promising drug target. However, cytoskeleton-targeting drugs often face the challenges of nonspecificity and drug resistance. Recent advancements in the field have tried to overcome these limitations through selective targeting, drug delivery systems, antibody–drug conjugates and combination therapies. Here we summarize the roles and regulatory mechanisms of the cytoskeleton in metastasis and discusse the current cytoskeleton-targeting therapies, including their mechanisms, clinical applications and limitations. Furthermore, this review suggests future directions for developing effective and safe cytoskeleton-based interventions against metastasis. Cancer spread, or metastasis, is a major challenge in treating cancer and often leads to death. This process involves cancer cells changing shape and moving through the body. The cytoskeleton, microtubules and intermediate filaments, helps cancer cells move and survive. Researchers have found that targeting the cytoskeleton could help stop cancer spread. However, drugs that target the cytoskeleton can also harm normal cells, causing side effects. Researchers reviewed how the cytoskeleton helps cancer cells spread and discussed current drugs targeting it. They highlighted issues with these drugs, such as toxicity and resistance. The study also explored new strategies to improve these treatments, combining them with other drugs or using advanced delivery systems such as nanoparticles. Researchers concluded that although targeting the cytoskeleton shows promise, more work is needed to make these treatments safer and more effective. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Roles of cytoskeleton in metastasis: from its mechanism to therapeutic strategies","authors":"Seyeon Lim, Soyeon Woo, Ki Won Lee, Kwang Dong Kim","doi":"10.1038/s12276-025-01608-9","DOIUrl":"10.1038/s12276-025-01608-9","url":null,"abstract":"The cytoskeleton is a dynamic intracellular protein network composed of actin filaments, microtubules and intermediate filaments that provides structural support in cells and plays a crucial role in tumor metastasis. Tumor cells encounter various dynamic mechanical environments during metastasis, and they adapt to these environments through cytoskeletal reorganization, which enables them to regulate cell morphology, generate intracellular forces and induce intracellular signaling. Actin filaments contribute to migration and extracellular matrix degradation by forming protrusive structures, such as lamellipodia, filopodia and invadopodia. Microtubules support migration, stabilize cell polarity and enhance survival under shear stress. Intermediate filaments maintain structural integrity and mechanical flexibility, allowing cancer cells to pass through narrow spaces. The cytoskeleton’s pivotal role in regulating metastasis makes it a promising drug target. However, cytoskeleton-targeting drugs often face the challenges of nonspecificity and drug resistance. Recent advancements in the field have tried to overcome these limitations through selective targeting, drug delivery systems, antibody–drug conjugates and combination therapies. Here we summarize the roles and regulatory mechanisms of the cytoskeleton in metastasis and discusse the current cytoskeleton-targeting therapies, including their mechanisms, clinical applications and limitations. Furthermore, this review suggests future directions for developing effective and safe cytoskeleton-based interventions against metastasis. Cancer spread, or metastasis, is a major challenge in treating cancer and often leads to death. This process involves cancer cells changing shape and moving through the body. The cytoskeleton, microtubules and intermediate filaments, helps cancer cells move and survive. Researchers have found that targeting the cytoskeleton could help stop cancer spread. However, drugs that target the cytoskeleton can also harm normal cells, causing side effects. Researchers reviewed how the cytoskeleton helps cancer cells spread and discussed current drugs targeting it. They highlighted issues with these drugs, such as toxicity and resistance. The study also explored new strategies to improve these treatments, combining them with other drugs or using advanced delivery systems such as nanoparticles. Researchers concluded that although targeting the cytoskeleton shows promise, more work is needed to make these treatments safer and more effective. 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":"1-13"},"PeriodicalIF":12.9,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01608-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913588","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 : 2026-01-07DOI: 10.1038/s12276-025-01609-8
Eojin Kim, Seoyoon Kim, Minseung Kim, Duyoung Min
The widespread adoption of artificial lighting has substantially increased human exposure to blue light across various environments, raising concerns about its potential adverse effects on human health. Over the past decades, blue light-induced biological responses have been investigated across multiple levels—from mechanistic studies of photoinduced reactive oxygen species generation to broader physiological consequences. Since all cellular and tissue-level effects ultimately originate from structural and functional alterations in molecular components, a comprehensive understanding of blue light-induced molecular damage is clearly warranted. This review summarizes current knowledge and recent findings on photooxidative molecular damage induced by blue light exposure, with a focus on the primary photochemical mechanisms of reactive oxygen species generation, blue light-sensitive endogenous photosensitizers, and the resulting oxidative damage to key biomolecules, including proteins, DNA and lipids. These insights collectively establish a more integrated framework for understanding how blue light compromises molecular integrity within cells. Sunlight is essential for life on Earth, comprising ultraviolet (UV), visible and infrared radiation. While the harmful effects of UV on the skin and eyes are well established, recent attention has turned to blue light—the high-energy portion of visible light—which is abundant in sunlight and also commonly emitted by digital screens and LED lighting. Experimental studies in human cells and animal models have shown that excessive blue light exposure can generate reactive oxygen species, leading to oxidative damage of DNA, proteins and lipids. Such molecular damage may contribute to skin photoaging and has been implicated as a potential factor in retinal disorders, including age-related macular degeneration. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Photooxidative molecular damage under blue light","authors":"Eojin Kim, Seoyoon Kim, Minseung Kim, Duyoung Min","doi":"10.1038/s12276-025-01609-8","DOIUrl":"10.1038/s12276-025-01609-8","url":null,"abstract":"The widespread adoption of artificial lighting has substantially increased human exposure to blue light across various environments, raising concerns about its potential adverse effects on human health. Over the past decades, blue light-induced biological responses have been investigated across multiple levels—from mechanistic studies of photoinduced reactive oxygen species generation to broader physiological consequences. Since all cellular and tissue-level effects ultimately originate from structural and functional alterations in molecular components, a comprehensive understanding of blue light-induced molecular damage is clearly warranted. This review summarizes current knowledge and recent findings on photooxidative molecular damage induced by blue light exposure, with a focus on the primary photochemical mechanisms of reactive oxygen species generation, blue light-sensitive endogenous photosensitizers, and the resulting oxidative damage to key biomolecules, including proteins, DNA and lipids. These insights collectively establish a more integrated framework for understanding how blue light compromises molecular integrity within cells. Sunlight is essential for life on Earth, comprising ultraviolet (UV), visible and infrared radiation. While the harmful effects of UV on the skin and eyes are well established, recent attention has turned to blue light—the high-energy portion of visible light—which is abundant in sunlight and also commonly emitted by digital screens and LED lighting. Experimental studies in human cells and animal models have shown that excessive blue light exposure can generate reactive oxygen species, leading to oxidative damage of DNA, proteins and lipids. Such molecular damage may contribute to skin photoaging and has been implicated as a potential factor in retinal disorders, including age-related macular degeneration. 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":"14-31"},"PeriodicalIF":12.9,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s12276-025-01609-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913507","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 : 2025-12-02DOI: 10.1038/s12276-025-01592-0
Kenichi Yoshida
Understanding the early stages of carcinogenesis requires detailed insight into the abnormalities present in normal cells before cancer onset. In the past, it was difficult to analyze genomic abnormalities in small clones in normal tissues. However, recent technological advances in genomic analysis have shed light on the process of accumulation of somatic mutations in normal cells, which is driven by factors such as aging and environmental influences. Even in normal tissues, clones that have acquired driver mutations-either directly contributing to carcinogenesis or adapting to specific pathological or genetic backgrounds-are frequently selected, leading to clonal expansion. Normal cells undergo clonal evolution into cancer cells over several decades, with the initial acquisition of a driver mutation occurring in early life. Here this review presents recent findings concerning the accumulation of somatic mutations in normal cells, acquisition of driver mutations and clonal evolution toward cancer.
{"title":"Somatic mutations and clonal evolution in normal tissues and cancer development.","authors":"Kenichi Yoshida","doi":"10.1038/s12276-025-01592-0","DOIUrl":"https://doi.org/10.1038/s12276-025-01592-0","url":null,"abstract":"<p><p>Understanding the early stages of carcinogenesis requires detailed insight into the abnormalities present in normal cells before cancer onset. In the past, it was difficult to analyze genomic abnormalities in small clones in normal tissues. However, recent technological advances in genomic analysis have shed light on the process of accumulation of somatic mutations in normal cells, which is driven by factors such as aging and environmental influences. Even in normal tissues, clones that have acquired driver mutations-either directly contributing to carcinogenesis or adapting to specific pathological or genetic backgrounds-are frequently selected, leading to clonal expansion. Normal cells undergo clonal evolution into cancer cells over several decades, with the initial acquisition of a driver mutation occurring in early life. Here this review presents recent findings concerning the accumulation of somatic mutations in normal cells, acquisition of driver mutations and clonal evolution toward cancer.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145662557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：