EMBO Molecular Medicine最新文献_第9页

Targeting FKBP51 prevents stress-induced preterm birth. 靶向FKBP51可预防应激性早产。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-01 Epub Date: 2025-03-17 DOI: 10.1038/s44321-025-00211-9

Ozlem Guzeloglu-Kayisli, Asli Ozmen, Busra Cetinkaya Un, Burak Un, Jacqueline Blas, Isabella Johnson, Andrea Thurman, Mark Walters, David Friend, Umit A Kayisli, Charles J Lockwood

{"title":"Targeting FKBP51 prevents stress-induced preterm birth.","authors":"Ozlem Guzeloglu-Kayisli, Asli Ozmen, Busra Cetinkaya Un, Burak Un, Jacqueline Blas, Isabella Johnson, Andrea Thurman, Mark Walters, David Friend, Umit A Kayisli, Charles J Lockwood","doi":"10.1038/s44321-025-00211-9","DOIUrl":"10.1038/s44321-025-00211-9","url":null,"abstract":"Preterm birth (PTB) is a leading cause of perinatal morbidity and mortality, with maternal stress-related disorders, such as depression and anxiety, linked to idiopathic PTB (iPTB). At the maternal-fetal interface, decidualized stromal cells (DSCs) exclusively express the progesterone receptor (PR) and play pivotal roles in maintaining pregnancy and initiating labor. DSCs also express FKBP51, a protein that binds to and inhibits transcriptional activity of glucocorticoid and PR receptors and is associated with stress-related diseases. We previously found that iPTB specimens exhibit increased FKBP51 levels and enhanced FKBP51-PR interactions in DSC nuclei. Additionally, we demonstrated that Fkbp5-deficient mice have prolonged gestation and are resistant to stress-induced PTB, suggesting that FKBP51 contributes to iPTB pathogenesis. Since no FDA-approved therapy exists for PTB, we hypothesized that inhibiting FKBP51 could prevent iPTB. Our current results show that the endogenous prostaglandin D2 derivative 15dPGJ2 reduces FKBP51 levels and FKBP51-PR interactions in cultured cells. Maternal stress increases uterine expression of Fkbp5, Oxtr, and Akr1c18, leading to shortened gestation. However, treatment with 15dPGJ2 lowers uterine Fkbp51, Oxtr, and Ptgs2 levels and prevents stress-induced PTB. Notably, co-treatment with 15dPGJ2 and either P4 or R5020 produced the most significant effects, highlighting the potential of 15dPGJ2 alone or in combination with progestins as a promising therapeutic strategy to prevent PTB.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"775-796"},"PeriodicalIF":9.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11982339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MHC-I upregulation by macbecin II in the solid tumors potentiates the effect of active immunotherapy. 实体瘤中 macbecin II 对 MHC-I 的上调增强了主动免疫疗法的效果。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-01 Epub Date: 2025-03-14 DOI: 10.1038/s44321-025-00213-7

Ravindra Pramod Deshpande, Kerui Wu, Shih-Ying Wu, Abhishek Tyagi, Eleanor C Smith, Jee-Won Kim, Kounosuke Watabe

{"title":"MHC-I upregulation by macbecin II in the solid tumors potentiates the effect of active immunotherapy.","authors":"Ravindra Pramod Deshpande, Kerui Wu, Shih-Ying Wu, Abhishek Tyagi, Eleanor C Smith, Jee-Won Kim, Kounosuke Watabe","doi":"10.1038/s44321-025-00213-7","DOIUrl":"10.1038/s44321-025-00213-7","url":null,"abstract":"We aimed to restore MHC-I expression on the surface of solid tumors including breast cancer and melanoma cells to regain sensitivity to immunotherapy and suppress metastatic progression. We screened a natural compound library and identified macbecin II as a reagent that upregulates MHC-I expression and induces antigen-dependent cell death in pre-invasive and invasive breast cancer models. Furthermore, we employed active immunotherapy using engineered small extracellular vesicles from dendritic cells (DCs) as a tumor vaccine (IL2-ep13nsEV) in combination with macbecin II for personalized breast cancer treatment. We found that macbecin II induced MHC-I-dependent antigen presentation and that IL2-ep13nsEV synergized with macbecin II inducing cell death, reducing metastasis, and boosting immune cell infiltration. In addition, macbecin II potentiated the effects of anti-PD-1 immunotherapy in suppressing tumor growth and metastasis. Mechanistically, macbecin II upregulated MHC-I expression post-translationally by rescuing it from lysosomal degradation. Our findings revealed a strong efficacy of macbecin II in regulating MHC-I expression and following antigen-dependent cell death. Therefore, combining active immunotherapies and macbecin II represents an effective strategy to prevent growth and progression of solid tumors including breast cancer and melanoma.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"797-822"},"PeriodicalIF":9.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11982318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Safe CAR-T: shedding light on CAR-related T-cell malignancies. 安全的 CAR-T：揭示与 CAR 相关的 T 细胞恶性肿瘤。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-01 Epub Date: 2025-02-28 DOI: 10.1038/s44321-025-00205-7

Qibin Liao, Jianqing Xu

引用次数: 0

AAV-mediated expression of proneural factors stimulates neurogenesis from adult Müller glia in vivo. aav介导的前神经因子的表达刺激成人<s:1>勒神经胶质细胞的神经发生。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-01 Epub Date: 2025-03-06 DOI: 10.1038/s44321-025-00209-3

Marina Pavlou, Marlene Probst, Lew Kaplan, Elizaveta Filippova, Aric R Prieve, Fred Rieke, Thomas A Reh

{"title":"AAV-mediated expression of proneural factors stimulates neurogenesis from adult Müller glia in vivo.","authors":"Marina Pavlou, Marlene Probst, Lew Kaplan, Elizaveta Filippova, Aric R Prieve, Fred Rieke, Thomas A Reh","doi":"10.1038/s44321-025-00209-3","DOIUrl":"10.1038/s44321-025-00209-3","url":null,"abstract":"The lack of regeneration in the human central nervous system (CNS) has major health implications. To address this, we previously used transgenic mouse models to show that neurogenesis can be stimulated in the adult mammalian retina by driving regeneration programs that other species activate following injury. Expression of specific proneural factors in adult Müller glia causes them to re-enter the cell cycle and give rise to new neurons following retinal injury. To bring this strategy closer to clinical application, we now show that neurogenesis can also be stimulated when delivering these transcription factors to Müller glia using adeno-associated viral (AAV) vectors. AAV-mediated neurogenesis phenocopies the neurogenesis we observed from transgenic animals, with different proneural factor combinations giving rise to distinct neuronal subtypes in vivo. Vector-borne neurons are morphologically, transcriptomically and physiologically similar to bipolar and amacrine/ganglion-like neurons. These results represent a key step forward in developing a cellular reprogramming approach for regenerative medicine in the CNS.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"722-746"},"PeriodicalIF":9.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11982270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pertussis before, during and after Covid-19. 在Covid-19之前、期间和之后的百日咳。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-04-01 Epub Date: 2025-02-24 DOI: 10.1038/s44321-025-00199-2

Camille Locht

{"title":"Pertussis before, during and after Covid-19.","authors":"Camille Locht","doi":"10.1038/s44321-025-00199-2","DOIUrl":"10.1038/s44321-025-00199-2","url":null,"abstract":"After the Covid-19 pandemic, pertussis has made a spectacular comeback in Europe and many other parts of the world, while during the pandemic it had essentially disappeared because of the social distancing requirements. However, even before the Covid-19 pandemic, the disease was on the rise in many countries, especially those that have replaced whole-cell pertussis vaccines by acellular pertussis vaccines. Several reasons may account for this upsurge, including strain adaptation to escape vaccine-induced immunity, rapid waning of immunity after vaccination and the failure of current vaccines to prevent infection by and transmission of the causative agent Bordetella pertussis. Various strategies have been deployed to control the disease, the most effective of which is maternal vaccination during pregnancy to protect the newborn against the most severe and deadly forms of the disease. However, ultimate control of pertussis likely requires novel vaccines, which prevent infection and transmission, not only disease. One of them is the live attenuated BPZE1 vaccine, which has shown promise in pre-clinical and clinical studies and may therefore perhaps become a gamechanger.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"594-598"},"PeriodicalIF":9.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11982557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lanatoside C activates the E3 ligase STUB1 to inhibit FOXP3 transcriptional activity and promote antitumor immunity. Lanatoside C激活E3连接酶STUB1，抑制FOXP3转录活性，促进抗肿瘤免疫。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-03-01 Epub Date: 2025-02-20 DOI: 10.1038/s44321-025-00200-y

Qian Zhou, Tong Yang, Xixi Yu, Bo Li, Jin Liu, Yongxin Mao, Rongxiang Guo, Zhuo Feng, Li Zhou, Guandi Zeng, Nan Li, Jinxia Liang, Lu Liu, Pengju Feng, Hong-Bing Shu, Liang Chen

{"title":"Lanatoside C activates the E3 ligase STUB1 to inhibit FOXP3 transcriptional activity and promote antitumor immunity.","authors":"Qian Zhou, Tong Yang, Xixi Yu, Bo Li, Jin Liu, Yongxin Mao, Rongxiang Guo, Zhuo Feng, Li Zhou, Guandi Zeng, Nan Li, Jinxia Liang, Lu Liu, Pengju Feng, Hong-Bing Shu, Liang Chen","doi":"10.1038/s44321-025-00200-y","DOIUrl":"10.1038/s44321-025-00200-y","url":null,"abstract":"Regulatory T cells (Tregs) play critical roles in inhibiting antitumor immunity, which is dependent on FOXP3-mediated transcriptional activity. However, no Treg-specific therapeutics has been approved for clinical use. We performed a high-throughput screen of FDA-approved drugs for potential inhibitors of FOXP3 transcriptional activity. These efforts identified Lanatoside C (Lac), which potently inhibits FOXP3 activity by causing degradation of RUNX1, a FOXP3-associated component required for its transcriptional activity. Lac directly binds the E3 ligase STUB1, leading to increased polyubiquitination and proteasomal degradation of RUNX1. Lac inhibits Tregs activity and promotes antitumor immunity in a mouse primary lung cancer model. In addition, Lac synergizes with PD-1 inhibitor to shrink lung cancers driven by mutant KRAS in a mouse model. Our findings suggested that the FDA-approved Lac is a Tregs inhibitor and serves as a candidate drug for cancer patients by its own or in combination with existing therapeutics such as PD-1 inhibitors.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"563-588"},"PeriodicalIF":9.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile. 利用一种安全的脑渗透药物利用胶质母细胞瘤的代谢脆弱性。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-03-01 Epub Date: 2025-02-03 DOI: 10.1038/s44321-025-00195-6

Audrey Burban, Cloe Tessier, Mathieu Larroquette, Joris Guyon, Cloe Lubiato, Mathis Pinglaut, Maxime Toujas, Johanna Galvis, Benjamin Dartigues, Emmanuelle Georget, H Artee Luchman, Samuel Weiss, David Cappellen, Nathalie Nicot, Barbara Klink, Macha Nikolski, Lucie Brisson, Thomas Mathivet, Andreas Bikfalvi, Thomas Daubon, Ahmad Sharanek

{"title":"Exploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile.","authors":"Audrey Burban, Cloe Tessier, Mathieu Larroquette, Joris Guyon, Cloe Lubiato, Mathis Pinglaut, Maxime Toujas, Johanna Galvis, Benjamin Dartigues, Emmanuelle Georget, H Artee Luchman, Samuel Weiss, David Cappellen, Nathalie Nicot, Barbara Klink, Macha Nikolski, Lucie Brisson, Thomas Mathivet, Andreas Bikfalvi, Thomas Daubon, Ahmad Sharanek","doi":"10.1038/s44321-025-00195-6","DOIUrl":"10.1038/s44321-025-00195-6","url":null,"abstract":"Glioblastoma is one of the most treatment-resistant and lethal cancers, with a subset of self-renewing brain tumour stem cells (BTSCs), driving therapy resistance and relapse. Here, we report that mubritinib effectively impairs BTSC stemness and growth. Mechanistically, bioenergetic assays and rescue experiments showed that mubritinib targets complex I of the electron transport chain, thereby impairing BTSC self-renewal and proliferation. Gene expression profiling and Western blot analysis revealed that mubritinib disrupts the AMPK/p27Kip1 pathway, leading to cell-cycle impairment. By employing in vivo pharmacokinetic assays, we established that mubritinib crosses the blood-brain barrier. Using preclinical patient-derived and syngeneic models, we demonstrated that mubritinib delays glioblastoma progression and extends animal survival. Moreover, combining mubritinib with radiotherapy or chemotherapy offers survival advantage to animals. Notably, we showed that mubritinib alleviates hypoxia, thereby enhancing ROS generation, DNA damage, and apoptosis in tumours when combined with radiotherapy. Encouragingly, toxicological and behavioural studies revealed that mubritinib is well tolerated and spares normal cells. Our findings underscore the promising therapeutic potential of mubritinib, warranting its further exploration in clinic for glioblastoma therapy.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"469-503"},"PeriodicalIF":9.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Model systems to study tumor-microbiome interactions in early-onset colorectal cancer. 研究早发性结直肠癌肿瘤-微生物组相互作用的模型系统。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-03-01 Epub Date: 2025-02-13 DOI: 10.1038/s44321-025-00198-3

Katharina M Richter, Marius Wrage, Carolin Krekeler, Tiago De Oliveira, Lena-Christin Conradi, Kerstin Menck, Annalen Bleckmann

{"title":"Model systems to study tumor-microbiome interactions in early-onset colorectal cancer.","authors":"Katharina M Richter, Marius Wrage, Carolin Krekeler, Tiago De Oliveira, Lena-Christin Conradi, Kerstin Menck, Annalen Bleckmann","doi":"10.1038/s44321-025-00198-3","DOIUrl":"10.1038/s44321-025-00198-3","url":null,"abstract":"Colorectal cancer (CRC) is a major health problem, with an alarming increase of early-onset CRC (EO-CRC) cases among individuals under 50 years of age. This trend shows the urgent need for understanding the underlying mechanisms leading to EO-CRC development and progression. There is significant evidence that the gut microbiome acts as a key player in CRC by triggering molecular changes in the colon epithelium, leading to tumorigenesis. However, a comprehensive collection and comparison of methods to study such tumor-microbiome interactions in the context of EO-CRC is sparse. This review provides an overview of the available in vivo, ex vivo as well as in vitro approaches to model EO-CRC and assess the effect of gut microbes on tumor development and growth. By comparing the advantages and limitations of each model system, it highlights that, while no single model is perfect, each is suitable for studying specific aspects of microbiome-induced tumorigenesis. Taken together, multifaceted approaches can simulate the human body's complexity, aiding in the development of effective treatment and prevention strategies for EO-CRC.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"395-413"},"PeriodicalIF":9.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

FABP4 as a therapeutic host target controlling SARS-CoV-2 infection. FABP4作为控制SARS-CoV-2感染的治疗性宿主靶点

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-03-01 Epub Date: 2025-01-22 DOI: 10.1038/s44321-024-00188-x

Hatoon Baazim, Emre Koyuncu, Gürol Tuncman, M Furkan Burak, Lea Merkel, Nadine Bahour, Ezgi Simay Karabulut, Grace Yankun Lee, Alireza Hanifehnezhad, Zehra Firat Karagoz, Katalin Földes, Ilayda Engin, Ayse Gokce Erman, Sidika Oztop, Nazlican Filazi, Buket Gul, Ahmet Ceylan, Ozge Ozgenc Cinar, Fusun Can, Hahn Kim, Ali Al-Hakeem, Hui Li, Fatih Semerci, Xihong Lin, Erkan Yilmaz, Onder Ergonul, Aykut Ozkul, Gökhan S Hotamisligil

{"title":"FABP4 as a therapeutic host target controlling SARS-CoV-2 infection.","authors":"Hatoon Baazim, Emre Koyuncu, Gürol Tuncman, M Furkan Burak, Lea Merkel, Nadine Bahour, Ezgi Simay Karabulut, Grace Yankun Lee, Alireza Hanifehnezhad, Zehra Firat Karagoz, Katalin Földes, Ilayda Engin, Ayse Gokce Erman, Sidika Oztop, Nazlican Filazi, Buket Gul, Ahmet Ceylan, Ozge Ozgenc Cinar, Fusun Can, Hahn Kim, Ali Al-Hakeem, Hui Li, Fatih Semerci, Xihong Lin, Erkan Yilmaz, Onder Ergonul, Aykut Ozkul, Gökhan S Hotamisligil","doi":"10.1038/s44321-024-00188-x","DOIUrl":"10.1038/s44321-024-00188-x","url":null,"abstract":"Host metabolic fitness is a critical determinant of infectious disease outcomes. Obesity, aging, and other related metabolic disorders are recognized as high-risk disease modifiers for respiratory infections, including coronavirus infections, though the underlying mechanisms remain unknown. Our study highlights fatty acid-binding protein 4 (FABP4), a key regulator of metabolic dysfunction and inflammation, as a modulator of SARS-CoV-2 pathogenesis, correlating strongly with disease severity in COVID-19 patients. We demonstrate that loss of FABP4 function, by genetic or pharmacological means, reduces SARS-CoV-2 replication and disrupts the formation of viral replication organelles in adipocytes and airway epithelial cells. Importantly, FABP4 inhibitor treatment of infected hamsters diminished lung viral titers, alleviated lung damage and reduced collagen deposition. These findings highlight the therapeutic potential of targeting host metabolism in limiting coronavirus replication and mitigating the pathogenesis of infection.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"414-440"},"PeriodicalIF":9.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Portimine A toxin causes skin inflammation through ZAKα-dependent NLRP1 inflammasome activation. Portimine A毒素通过zak α依赖性NLRP1炎性体激活引起皮肤炎症。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-03-01 Epub Date: 2025-02-13 DOI: 10.1038/s44321-025-00197-4

Léana Gorse, Loïc Plessis, Stephen Wearne, Margaux Paradis, Miriam Pinilla, Rae Chua, Seong Soo Lim, Elena Pelluz, Gee-Ann Toh, Raoul Mazars, Caio Bomfim, Fabienne Hervé, Korian Lhaute, Damien Réveillon, Bastien Suire, Léa Ravon-Katossky, Thomas Benoist, Léa Fromont, David Péricat, Kenneth Neil Mertens, Amélie Derrien, Aouregan Terre-Terrillon, Nicolas Chomérat, Gwenaël Bilien, Véronique Séchet, Liliane Carpentier, Mamadou Fall, Amidou Sonko, Hadi Hakim, Nfally Sadio, Jessie Bourdeaux, Céline Cougoule, Anthony K Henras, Ana Belen Perez-Oliva, Patrice Brehmer, Francisco J Roca, Franklin L Zhong, John Common, Etienne Meunier, Philipp Hess

{"title":"Portimine A toxin causes skin inflammation through ZAKα-dependent NLRP1 inflammasome activation.","authors":"Léana Gorse, Loïc Plessis, Stephen Wearne, Margaux Paradis, Miriam Pinilla, Rae Chua, Seong Soo Lim, Elena Pelluz, Gee-Ann Toh, Raoul Mazars, Caio Bomfim, Fabienne Hervé, Korian Lhaute, Damien Réveillon, Bastien Suire, Léa Ravon-Katossky, Thomas Benoist, Léa Fromont, David Péricat, Kenneth Neil Mertens, Amélie Derrien, Aouregan Terre-Terrillon, Nicolas Chomérat, Gwenaël Bilien, Véronique Séchet, Liliane Carpentier, Mamadou Fall, Amidou Sonko, Hadi Hakim, Nfally Sadio, Jessie Bourdeaux, Céline Cougoule, Anthony K Henras, Ana Belen Perez-Oliva, Patrice Brehmer, Francisco J Roca, Franklin L Zhong, John Common, Etienne Meunier, Philipp Hess","doi":"10.1038/s44321-025-00197-4","DOIUrl":"10.1038/s44321-025-00197-4","url":null,"abstract":"In 2020-2021, a \"mysterious illness\" struck Senegalese fishermen, causing severe acute dermatitis in over one thousand individuals following exposure through drift-net fishing activity. Here, by performing deep analysis of the environmental samples we reveal the presence of the marine dinoflagellate Vulcanodinium rugosum and its associated cyclic imine toxins. Specifically, we show that the toxin PortimineA, strongly enriched in environmental samples, impedes ribosome function in human keratinocytes, which subsequently activates the stress kinases ZAKα and P38 and promotes the nucleation of the human NLRP1 inflammasome, leading to the release of IL-1β/IL-18 pro-inflammatory cytokines and cell death. Furthermore, cell-based models highlight that naturally occurring mutations in the P38-targeted sites of human NLRP1 are unable to respond to PortimineA exposure. Finally, the development and use of human organotypic skins and zebrafish models of PortimineA exposure demonstrate that the ZAKα-NLRP1 axis drives skin necrosis and inflammation. Our results exemplify the threats to human health caused by emerging environmental toxins and identify ZAKα and NRLP1 as important pharmacological targets to mitigate PortimineA toxicity.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"535-562"},"PeriodicalIF":9.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0