EMBO Molecular Medicine最新文献

Pyrimidine addiction: an Achilles' heel of NF2-altered mesothelioma. 嘧啶成瘾：nf2改变的间皮瘤的致命弱点。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-07-24 DOI: 10.1038/s44321-025-00276-6

Jianlong Jia,Georgios T Stathopoulos

引用次数: 0

De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma. 在缺乏nf2的间皮瘤中，从头合成嘧啶是一种附带代谢易感性。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-07-24 DOI: 10.1038/s44321-025-00278-4

Duo Xu,Yanyun Gao,Shengchen Liu,Shiyuan Yin,Tong Hu,Haibin Deng,Tuo Zhang,Balazs Hegedüs,Thomas M Marti,Patrick Dorn,Shun-Qing Liang,Ralph A Schmid,Ren-Wang Peng,Yongqian Shu

{"title":"De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma.","authors":"Duo Xu,Yanyun Gao,Shengchen Liu,Shiyuan Yin,Tong Hu,Haibin Deng,Tuo Zhang,Balazs Hegedüs,Thomas M Marti,Patrick Dorn,Shun-Qing Liang,Ralph A Schmid,Ren-Wang Peng,Yongqian Shu","doi":"10.1038/s44321-025-00278-4","DOIUrl":"https://doi.org/10.1038/s44321-025-00278-4","url":null,"abstract":"Pleural mesothelioma (PM) is one of the deadliest cancers, with limited therapeutic options due to its therapeutically intractable genome, which is characterized by the functional inactivation of tumor suppressor genes (TSGs) and high tumor heterogeneity, including diverse metabolic adaptations. However, the molecular mechanisms underlying these metabolic alterations remain poorly understood, particularly how TSG inactivation rewires tumor metabolism to drive tumorigenesis and create metabolic dependencies. Through integrated multi-omics analysis, we identify for the first time that NF2 loss of function defines a distinct PM subtype characterized by enhanced de novo pyrimidine synthesis, which NF2-deficient PM cells are critically dependent on for sustained proliferation in vitro and in vivo. Mechanistically, NF2 loss activates YAP, a downstream proto-oncogenic transcriptional coactivator in the Hippo signalling pathway, which in turn upregulates CAD and DHODH, key enzymes in the de novo pyrimidine biosynthesis pathway. Our findings provide novel insights into metabolic reprogramming in PM, revealing de novo pyrimidine synthesis as a synthetic lethal vulnerability in NF2-deficient tumors. This work highlights a potential therapeutic strategy for targeting NF2-deficient mesothelioma through metabolic intervention.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"34 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

miR-33 inhibition as a novel therapeutic approach for treating muscular dystrophy. miR-33抑制作为一种治疗肌营养不良的新方法。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-07-23 DOI: 10.1038/s44321-025-00271-x

Michael A Lopez,Matthew S Alexander

引用次数: 0

JAK/STAT inhibition protects glucocorticoid receptor knockout mice from lethal malaria-induced hypoglycemia and hyperinflammation. JAK/STAT抑制可保护糖皮质激素受体敲除小鼠免于疟疾致死性低血糖和高炎症。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-07-23 DOI: 10.1038/s44321-025-00264-w

Fran Prenen,Leen Vandermosten,Sofie Knoops,Emilie Pollenus,Hendrik Possemiers,Pauline Dagneau de Richecour,Giorgio Caratti,Christopher Cawthorne,Sabine Vettorazzi,Yevva Cranshoff,Dominique Schols,Sandra Claes,Christophe M Deroose,Uwe Himmelreich,Jan Tuckermann,Philippe E Van den Steen

{"title":"JAK/STAT inhibition protects glucocorticoid receptor knockout mice from lethal malaria-induced hypoglycemia and hyperinflammation.","authors":"Fran Prenen,Leen Vandermosten,Sofie Knoops,Emilie Pollenus,Hendrik Possemiers,Pauline Dagneau de Richecour,Giorgio Caratti,Christopher Cawthorne,Sabine Vettorazzi,Yevva Cranshoff,Dominique Schols,Sandra Claes,Christophe M Deroose,Uwe Himmelreich,Jan Tuckermann,Philippe E Van den Steen","doi":"10.1038/s44321-025-00264-w","DOIUrl":"https://doi.org/10.1038/s44321-025-00264-w","url":null,"abstract":"Disease tolerance is a key defense mechanism that limits damage to the host without directly reducing pathogen levels. In malaria, these mechanisms are essential for preventing severe disease and death but remain poorly understood. In this study, we show that glucocorticoid receptor (GR)-mediated processes play a vital role in disease tolerance during Plasmodium chabaudi AS infection. GR deletion in infected mice resulted in lethal hypoglycemia and a cytokine storm. Hypoglycemia was driven by severe metabolic dysfunction in the liver and spleen, characterized by increased glucose uptake, glycogen depletion, a dominant glycolytic profile and reduced gluconeogenic gene expression. Importantly, this hypoglycemic state was strongly associated with overactivation of the JAK/STAT pathway and excessive cytokine expression. Treatment with the JAK1/2 inhibitor ruxolitinib significantly improved survival by preventing lethal hypoglycemia and suppressing hyperinflammation. Our findings reveal a novel link between GR signaling, STAT3 activation, cytokine expression and glucose metabolism during severe malaria. This underscores the critical role of GR-mediated processes in disease tolerance and highlights ruxolitinib as a promising adjuvant therapy for managing life-threatening metabolic complications in malaria.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"17 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MicroRNA-33 inhibition ameliorates muscular dystrophy by enhancing skeletal muscle regeneration. 抑制MicroRNA-33通过增强骨骼肌再生来改善肌肉萎缩症。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-07-23 DOI: 10.1038/s44321-025-00273-9

Naoya Sowa,Takahiro Horie,Yuya Ide,Osamu Baba,Kengo Kora,Takeshi Yoshida,Yujiro Nakamura,Shigenobu Matsumura,Kazuki Matsushita,Miyako Imanaka,Fuquan Zou,Eitaro Kume,Hidenori Kojima,Qiuxian Qian,Kayo Kimura,Ryotaro Otsuka,Noriko Hara,Tomohiro Yamasaki,Chiharu Otani,Yuta Tsujisaka,Tomohide Takaya,Chika Nishimura,Dai Watanabe,Koji Hasegawa,Jun Kotera,Kozo Oka,Ryo Fujita,Akihiro Takemiya,Takashi Sasaki,Yuuya Kasahara,Satoshi Obika,Takeshi Kimura,Koh Ono

{"title":"MicroRNA-33 inhibition ameliorates muscular dystrophy by enhancing skeletal muscle regeneration.","authors":"Naoya Sowa,Takahiro Horie,Yuya Ide,Osamu Baba,Kengo Kora,Takeshi Yoshida,Yujiro Nakamura,Shigenobu Matsumura,Kazuki Matsushita,Miyako Imanaka,Fuquan Zou,Eitaro Kume,Hidenori Kojima,Qiuxian Qian,Kayo Kimura,Ryotaro Otsuka,Noriko Hara,Tomohiro Yamasaki,Chiharu Otani,Yuta Tsujisaka,Tomohide Takaya,Chika Nishimura,Dai Watanabe,Koji Hasegawa,Jun Kotera,Kozo Oka,Ryo Fujita,Akihiro Takemiya,Takashi Sasaki,Yuuya Kasahara,Satoshi Obika,Takeshi Kimura,Koh Ono","doi":"10.1038/s44321-025-00273-9","DOIUrl":"https://doi.org/10.1038/s44321-025-00273-9","url":null,"abstract":"Muscular dystrophy is a group of diseases characterized by progressive weakness and degeneration of skeletal muscles, for which there is currently no cure. Here, we show that microRNA (miR)-33a/b play a crucial role in muscle regeneration. miR-33a was upregulated during myoblast differentiation and in skeletal muscles of mdx mice, a genetic model of Duchenne muscular dystrophy (DMD). miR-33a deficiency enhanced muscle regeneration response to cardiotoxin injury and attenuated muscle degeneration and fibrosis in mdx mice. Conversely, a humanized mouse model expressing miR-33a and miR-33b showed exacerbated muscle degeneration and fibrosis. Mechanistically, miR-33a/b inhibited satellite cell proliferation, leading to reduced muscle regeneration and increased fibrosis by targeting Cdk6, Fst, and Abca1. Local and systemic administration of anti-miRNA oligonucleotides targeting miR-33a/b ameliorated the dystrophic phenotype in mdx mice. Furthermore, miR-33b inhibition upregulated these target genes in myotubes differentiated from human induced pluripotent stem cells derived from a patient with DMD. These findings indicate that miR-33a/b are involved in muscle regeneration and their inhibition may represent a potential therapeutic strategy for muscular dystrophy.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"15 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PV-1: a novel molecular prognostic marker of distant metastases in various solid tumors. PV-1：各种实体瘤远处转移的新分子预后标志物。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-07-21 DOI: 10.1038/s44321-025-00277-5

Chiara Pozzi,Riccardo Sarti,Antonino Lo Cascio,Stefanos Bonovas,Luca Tiraboschi,Michela Lizier,Alice Bertocchi,Rosalba Torrisi,Bethania Fernandes,Piergiuseppe Colombo,Pietro Diana,Emilia Maria Cristina Mazza,Marina Valeri,Salvatore Lorenzo Renne,Ferdinando Carlo Maria Cananzi,Laura Samà,Alexia Bertuzzi,Corrado Tinterri,Massimo Lazzeri,Maria Rescigno

{"title":"PV-1: a novel molecular prognostic marker of distant metastases in various solid tumors.","authors":"Chiara Pozzi,Riccardo Sarti,Antonino Lo Cascio,Stefanos Bonovas,Luca Tiraboschi,Michela Lizier,Alice Bertocchi,Rosalba Torrisi,Bethania Fernandes,Piergiuseppe Colombo,Pietro Diana,Emilia Maria Cristina Mazza,Marina Valeri,Salvatore Lorenzo Renne,Ferdinando Carlo Maria Cananzi,Laura Samà,Alexia Bertuzzi,Corrado Tinterri,Massimo Lazzeri,Maria Rescigno","doi":"10.1038/s44321-025-00277-5","DOIUrl":"https://doi.org/10.1038/s44321-025-00277-5","url":null,"abstract":"Identification of biomarkers for the hematogenous spreading of cancer cells is of paramount prognostic and therapeutic value. We showed that Plasmalemma Vesicle Associated Protein-1 (PV-1) serves as a marker of increased blood vessel permeability and is an independent predictor of colorectal cancer dissemination. This study investigates whether PV-1 can also act as a prognostic marker for distant metastases in other solid tumors. We analyzed samples from 134 patients: 30 luminal breast cancer (BC), 52 clear cell renal cell carcinoma (ccRCC), and obtained preliminary data from 52 soft tissue sarcomas (STS). A higher frequency of PV-1+ endothelial cells was significantly associated with metastatic progression in luminal BC and ccRCC. Moreover, the frequency of PV-1+ cells emerged as a significant prognostic factor for metastasis-free survival in both luminal BC and ccRCC. Further research is needed to validate PV-1's prognostic utility, as including it at diagnosis may change the management of these patients and should allow stratification for more aggressive therapies or for closer follow-ups to promptly intervene in case of metastases development.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"6 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144678102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Peptidomic analysis of CSF reveals new biomarker candidates for amyotrophic lateral sclerosis. 脑脊液的肽组学分析揭示了肌萎缩侧索硬化症的新生物标志物候选物。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-07-18 DOI: 10.1038/s44321-025-00272-w

Besnik Muqaku,Johannes Dorst,Maximilian Wiesenfarth,Markus Otto,Albert C Ludolph,Patrick Oeckl

{"title":"Peptidomic analysis of CSF reveals new biomarker candidates for amyotrophic lateral sclerosis.","authors":"Besnik Muqaku,Johannes Dorst,Maximilian Wiesenfarth,Markus Otto,Albert C Ludolph,Patrick Oeckl","doi":"10.1038/s44321-025-00272-w","DOIUrl":"https://doi.org/10.1038/s44321-025-00272-w","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, and novel biomarkers are needed. We applied mass-spectrometry-based peptidomic analysis in cerebrospinal fluid (CSF) samples of ALS and non-neurodegenerative control patients (Con) from a discovery (n = 48) and validation (n = 109) cohort for biomarker discovery. Systematic selection revealed a panel of eight novel peptide biomarker candidates for ALS (out of 33,605) derived from seven proteins. In the validation cohort, NFL, MAP1B, MYL1, and APOC1 peptides were upregulated, and peptides from CADM3, SCG1, and PENK were downregulated in ALS compared to Con. The peptides (except NFL) were not changed in other neurodegenerative diseases, including Alzheimer´s disease, frontotemporal dementia and Parkinson´s disease. Combination of all peptides in a logistic regression model led to an area under the curve value of 98% for the discrimination of ALS from controls. Data of the NFL peptide strongly correlated with an established NFL immunoassay (Ella, r = 0.97). The peptide biomarker candidates are derived from proteins with different function, and their determination with our method provides the opportunity for simultaneous investigation of key processes in ALS.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"52 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

LIMA1-alpha staining predicts curative intent surgery response in HPV negative head and neck cancer. lima1 - α染色预测HPV阴性头颈癌的治疗意图手术反应。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-07-17 DOI: 10.1038/s44321-025-00266-8

Xi Qiao,Johannes Routila,Mari Tienhaara,Heikki Irjala,Priyadharshini Parimelazhagan Santhi,Teemu Huusko,Linda Nissi,Ilkka Paatero,Noora Lehtinen,Juha Rantala,Toni Viljanen,Ilmo Leivo,Petri Koivunen,Anna Jouppila-Mättö,Rami Taulu,Leif Bäck,Tommy Wilkman,Eeva Haapio,Ilpo Kinnunen,Kari Kurppa,Jukka Westermarck,Sami Ventelä

{"title":"LIMA1-alpha staining predicts curative intent surgery response in HPV negative head and neck cancer.","authors":"Xi Qiao,Johannes Routila,Mari Tienhaara,Heikki Irjala,Priyadharshini Parimelazhagan Santhi,Teemu Huusko,Linda Nissi,Ilkka Paatero,Noora Lehtinen,Juha Rantala,Toni Viljanen,Ilmo Leivo,Petri Koivunen,Anna Jouppila-Mättö,Rami Taulu,Leif Bäck,Tommy Wilkman,Eeva Haapio,Ilpo Kinnunen,Kari Kurppa,Jukka Westermarck,Sami Ventelä","doi":"10.1038/s44321-025-00266-8","DOIUrl":"https://doi.org/10.1038/s44321-025-00266-8","url":null,"abstract":"In many solid cancer types, surgery alone could be a sufficient first therapy option for a significant number of cancer patients. However, there are currently no diagnostic solutions to identify patients who could be stratified to surgery alone. To identify a biomarker predicting cancer surgery response, candidate biomarkers were studied in a non-metastatic head and neck squamous cell carcinoma (nmHNSCC) cohort well representative of the HPV-negative patient population. LIMA1 immunohistochemistry (IHC) with specificity-validated antibodies outperformed all other biomarkers in multivariable survival analyses of patients with nmHNSCC (n = 128, HR 2.10, P = 0.006). The prognostic effect was selective to LIMA1-alpha isoform IHC detection in patients who had received surgical therapy (n = 184, HR 2.39, P > 0.001). Strikingly, our real-world validation results, using two prospectively collected cohorts (n = 15 and n = 86), demonstrate that none of the LIMA1 negative patients died of HNSCC during the follow-up. Collectively, we report here the discovery of a diagnostic LIMA1-alpha IHC assay for HPV-negative HNSCC patient stratification to surgery-only therapy. Application of LIMA1 detection in routine nmHNSCC diagnostics would revolutionize the clinical management of HNSCC patients.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"18 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cold exposure promotes the progression of osteoarthritis through downregulating APOE in cartilage. 冷暴露通过下调软骨中的APOE促进骨关节炎的进展。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-07-15 DOI: 10.1038/s44321-025-00268-6

Yueqi Zhang,Mei Fu,Chun Zhou,Xiao Wang,Zengxin Jiang,Chang Jiang,Shengyang Guo,Zhiying Pang,Chenzhong Wang,Tao Yu,Senbo An,Xiuhui Wang,Zhe Wang

{"title":"Cold exposure promotes the progression of osteoarthritis through downregulating APOE in cartilage.","authors":"Yueqi Zhang,Mei Fu,Chun Zhou,Xiao Wang,Zengxin Jiang,Chang Jiang,Shengyang Guo,Zhiying Pang,Chenzhong Wang,Tao Yu,Senbo An,Xiuhui Wang,Zhe Wang","doi":"10.1038/s44321-025-00268-6","DOIUrl":"https://doi.org/10.1038/s44321-025-00268-6","url":null,"abstract":"Osteoarthritis (OA) is a degenerative joint disease with limited effective therapies. Cold weathers have been shown to affect joint pain in OA patients. However, the impact of cold climate on OA progression is debated, with the underlying mechanisms not fully understood. This study aims to elucidate the role of Apolipoprotein E (Apoe) in chondrocytes in relation to OA progression under cold exposure. Both human chondrocytes RNA sequencing and DMM mice OA model revealed that lower temperatures significantly downregulated Apoe expression, correlating with OA exacerbation. Conditional knockout of Apoe in cartilage aggravated cartilage degeneration, leading to lipid accumulation, increased ROS production, mitochondrial dysfunction, and elevated chondrocyte apoptosis. Treatment with RGX-104, an LXRβ agonist, reversely restored APOE expression, mitigated aberrant lipid accumulation and countered the detrimental effects of cold exposure on OA progression. These results suggest that targeting lipid transfer and metabolism, especially through Apoe modulation, may offer therapeutic strategies for OA patients residing in colder climates, such as those at high altitudes and latitudes, and even winter season.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"12 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effects of antioxidants on cancer progression. 抗氧化剂对癌症进展的影响。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2025-07-11 DOI: 10.1038/s44321-025-00269-5

Sarah Schmidt,Xi Qiao,Martin O Bergö

引用次数: 0