Pub Date : 2026-02-01Epub Date: 2026-01-08DOI: 10.1038/s44321-025-00369-2
Debajyoti Das, Amanda Wyatt, Sarath Sivaprasad, Vanessa Wahl, Sen Qiao, Fabien Ectors, Zulfiah M Moosa, Claire L Newton, Mario Fritz, Robert P Millar, Ulrich Boehm
G protein-coupled receptors (GPCRs) carry out the majority of cellular transmembrane signaling. Many pathologies have underlying GPCR mutations, most of which cause misfolding and GPCR cell surface trafficking failure. Large libraries of existing small molecule GPCR ligands could be repurposed as pharmacological chaperones (PCs) which restore mutant GPCR folding and function, presenting an exciting alternative to complex gene repair, yet such in vivo studies are limited. Therefore, as proof-of-concept, we use one such known ligand/PC, Org42599/Org43553, to show functional rescue in mice bearing an inactivating human luteinizing hormone receptor (LHR) mutation. Mutant males had delayed puberty and Leydig cell LHR signaling impairment, however, fertility was unaffected. Mutant females had irregular estrous cycles, anovulation, abrogated ovarian LHR signaling, and complete infertility. PC treatment of mutant females restored LH signaling and estrous cyclicity. To characterize treatment efficacy, we developed an AI algorithm that reliably identified inherent differences among experimental groups, enabling functional analysis of the treatment effect in vivo. Our data set the stage to integrate AI analysis with GPCR-targeting PC molecules to treat diverse GPCR-based diseases.
{"title":"Functional rescue and AI analysis of a human inactivating GPCR mutation using a small molecule.","authors":"Debajyoti Das, Amanda Wyatt, Sarath Sivaprasad, Vanessa Wahl, Sen Qiao, Fabien Ectors, Zulfiah M Moosa, Claire L Newton, Mario Fritz, Robert P Millar, Ulrich Boehm","doi":"10.1038/s44321-025-00369-2","DOIUrl":"10.1038/s44321-025-00369-2","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) carry out the majority of cellular transmembrane signaling. Many pathologies have underlying GPCR mutations, most of which cause misfolding and GPCR cell surface trafficking failure. Large libraries of existing small molecule GPCR ligands could be repurposed as pharmacological chaperones (PCs) which restore mutant GPCR folding and function, presenting an exciting alternative to complex gene repair, yet such in vivo studies are limited. Therefore, as proof-of-concept, we use one such known ligand/PC, Org42599/Org43553, to show functional rescue in mice bearing an inactivating human luteinizing hormone receptor (LHR) mutation. Mutant males had delayed puberty and Leydig cell LHR signaling impairment, however, fertility was unaffected. Mutant females had irregular estrous cycles, anovulation, abrogated ovarian LHR signaling, and complete infertility. PC treatment of mutant females restored LH signaling and estrous cyclicity. To characterize treatment efficacy, we developed an AI algorithm that reliably identified inherent differences among experimental groups, enabling functional analysis of the treatment effect in vivo. Our data set the stage to integrate AI analysis with GPCR-targeting PC molecules to treat diverse GPCR-based diseases.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"725-758"},"PeriodicalIF":8.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12905377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932699","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}
Pub Date : 2026-02-01Epub Date: 2026-01-16DOI: 10.1038/s44321-025-00366-5
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":"Correction to: 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/s44321-025-00366-5","DOIUrl":"10.1038/s44321-025-00366-5","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"851-854"},"PeriodicalIF":8.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12905169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988892","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}
Oocyte activation is essential for successful fertilization and subsequent embryonic development. However, only a few disease-causing genes have been associated with sperm-derived oocyte activation failure, and the underlying molecular mechanisms and therapeutic approaches remain largely unknown. Here, we identified pathogenic mutations in HNRNPR from three infertile patients whose partners repeatedly failed to achieve transferable embryos despite undergoing both in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Remarkably, artificial oocyte activation (AOA, Srcl₂) combined with ICSI successfully restored fertilization. Whole-exome sequencing revealed HNRNPR mutations shared among affected families. To establish causality, we generated a knock-in mouse model, in which males exhibited phenotypes consistent with those observed in patients. Mechanistically, ICSI with sperm from Hnrnpr-mutated mice was unable to induce normal calcium oscillations in oocytes, while spermatozoa from both humans and mice exhibited reduced expression and mislocalization of phospholipase C zeta (PLCζ). Further analyses demonstrated that hnRNPR regulates Plcz1 splicing in an m6A-dependent manner. Beyond Srcl₂ treatment, we also developed NusA-PLCζ to effectively restore oocyte activation. Collectively, these findings reveal a previously unrecognized molecular mechanism by which HNRNPR mutations cause sperm-borne oocyte activation failure and male infertility, while highlighting targeted therapeutic strategies to restore fertilization.
{"title":"Characterization and therapy of fertilization failure in murine and human models with HNRNPR mutations.","authors":"Shiming Gan,Yangyang Li,Lin Yin,Xiaotong Yang,Chen Lou,Sisi Li,Mingde Lin,Xin Li,Wenchao Xu,Jiaming Zhou,Peiran Hu,Zhendong Yao,Yuan Yuan,Jianzhong Sheng,Chen Zhang,Wei Yang,Youjiang Li,Hefeng Huang","doi":"10.1038/s44321-026-00374-z","DOIUrl":"https://doi.org/10.1038/s44321-026-00374-z","url":null,"abstract":"Oocyte activation is essential for successful fertilization and subsequent embryonic development. However, only a few disease-causing genes have been associated with sperm-derived oocyte activation failure, and the underlying molecular mechanisms and therapeutic approaches remain largely unknown. Here, we identified pathogenic mutations in HNRNPR from three infertile patients whose partners repeatedly failed to achieve transferable embryos despite undergoing both in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Remarkably, artificial oocyte activation (AOA, Srcl₂) combined with ICSI successfully restored fertilization. Whole-exome sequencing revealed HNRNPR mutations shared among affected families. To establish causality, we generated a knock-in mouse model, in which males exhibited phenotypes consistent with those observed in patients. Mechanistically, ICSI with sperm from Hnrnpr-mutated mice was unable to induce normal calcium oscillations in oocytes, while spermatozoa from both humans and mice exhibited reduced expression and mislocalization of phospholipase C zeta (PLCζ). Further analyses demonstrated that hnRNPR regulates Plcz1 splicing in an m6A-dependent manner. Beyond Srcl₂ treatment, we also developed NusA-PLCζ to effectively restore oocyte activation. Collectively, these findings reveal a previously unrecognized molecular mechanism by which HNRNPR mutations cause sperm-borne oocyte activation failure and male infertility, while highlighting targeted therapeutic strategies to restore fertilization.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"2 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089135","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}
Pub Date : 2026-01-20DOI: 10.1038/s44321-026-00372-1
Precious Cramer,Stefan F H Neys,Manuela Fiedler,Raquel Lorenzetti,Henrike Reinhard,Iga Janowska,Julian Staniek,Ann-Katrin Kohl,Petra Hadlova,Magdalena Huber,Bodo Plachter,Clarissa Read,Valeria Falcone,Jens von Einem,Katja Hoffmann,Tihana Lenac Rovis,Stipan Jonjic,Philipp Kolb,Marta Rizzi,Hartmut Hengel
Virus infections elicit long-term IgG antibody and memory responses. Human cytomegalovirus (HCMV) is widespread in humans and disseminates despite the presence of virus-specific antibodies. Here, we report that the HCMV Fcγ-binding glycoprotein 34 modulates humoral immunity by binding to IgG⁺ memory B cells. gp34-B cell receptor (BCR) interaction initiates activation of the PDK1/AKT/mTOR/S6 pathway and BCR internalization in a SYK-independent manner. Prolonged stimulation also induces B-cell activation via upregulation of CD69 and CD86. In a T-cell-dependent response, however, interaction with gp34 blocks B-cell proliferation, differentiation into plasmablasts, and soluble IgG production, while stimulating TNF-α secretion. Through gp34 stimulation on IgG⁺ B cells, neighboring IgM⁺ and IgA⁺ B cells are likewise impaired in proliferation, plasmablast formation, and immunoglobulin secretion. In summary, gp34 specifically interacts with IgG⁺ memory B cells, inducing a hyporesponsive state across the B-cell compartment through direct and indirect regulation. This reveals a novel mode of viral evasion from B-cell responses by suppressing secondary immunity.
病毒感染引起长期的IgG抗体和记忆反应。人类巨细胞病毒（HCMV）在人类中广泛传播，尽管存在病毒特异性抗体。在这里，我们报告了HCMV fc γ-结合糖蛋白34通过结合IgG +记忆B细胞来调节体液免疫。gp34-B细胞受体（BCR）相互作用启动PDK1/AKT/mTOR/S6通路的激活，并以不依赖syk的方式内化BCR。长时间的刺激也通过上调CD69和CD86诱导b细胞活化。然而，在t细胞依赖性反应中，与gp34的相互作用阻断了b细胞的增殖、向质母细胞的分化和可溶性IgG的产生，同时刺激TNF-α的分泌。通过gp34刺激IgG + B细胞，邻近的IgM +和IgA + B细胞的增殖、成浆细胞形成和免疫球蛋白分泌也同样受到损害。综上所述，gp34特异地与IgG⁺记忆性B细胞相互作用，通过直接和间接调控诱导整个B细胞隔室的低反应状态。这揭示了一种通过抑制二次免疫逃避b细胞应答的新模式。
{"title":"A viral glycoprotein targets IgG+ memory B cells to mediate humoral immune evasion.","authors":"Precious Cramer,Stefan F H Neys,Manuela Fiedler,Raquel Lorenzetti,Henrike Reinhard,Iga Janowska,Julian Staniek,Ann-Katrin Kohl,Petra Hadlova,Magdalena Huber,Bodo Plachter,Clarissa Read,Valeria Falcone,Jens von Einem,Katja Hoffmann,Tihana Lenac Rovis,Stipan Jonjic,Philipp Kolb,Marta Rizzi,Hartmut Hengel","doi":"10.1038/s44321-026-00372-1","DOIUrl":"https://doi.org/10.1038/s44321-026-00372-1","url":null,"abstract":"Virus infections elicit long-term IgG antibody and memory responses. Human cytomegalovirus (HCMV) is widespread in humans and disseminates despite the presence of virus-specific antibodies. Here, we report that the HCMV Fcγ-binding glycoprotein 34 modulates humoral immunity by binding to IgG⁺ memory B cells. gp34-B cell receptor (BCR) interaction initiates activation of the PDK1/AKT/mTOR/S6 pathway and BCR internalization in a SYK-independent manner. Prolonged stimulation also induces B-cell activation via upregulation of CD69 and CD86. In a T-cell-dependent response, however, interaction with gp34 blocks B-cell proliferation, differentiation into plasmablasts, and soluble IgG production, while stimulating TNF-α secretion. Through gp34 stimulation on IgG⁺ B cells, neighboring IgM⁺ and IgA⁺ B cells are likewise impaired in proliferation, plasmablast formation, and immunoglobulin secretion. In summary, gp34 specifically interacts with IgG⁺ memory B cells, inducing a hyporesponsive state across the B-cell compartment through direct and indirect regulation. This reveals a novel mode of viral evasion from B-cell responses by suppressing secondary immunity.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"142 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005396","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}
Despite major advances in the clinical management of non-small cell lung carcinoma (NSCLC), most patients treated with first-line platinum-based chemotherapy combined with immune checkpoint inhibitors will relapse, which constitutes an unmet medical need. Here, we found that various DNA damage inducers increase the levels of Notch Intracellular Domain (NICD), the active form of NOTCH1. Mechanistically, we revealed that, upon platinum treatment, the expression levels of both MDM2 and NICD were increased and that MDM2 stabilised NICD through ubiquitination. Using NSCLC patient-derived xenografts displaying intrinsic carboplatin resistance, we demonstrated that combining carboplatin with a γ-secretase inhibitor, which hinders NICD generation, significantly improves survival and reduces tumour growth compared with carboplatin monotherapy. Furthermore, in patients with NSCLC who received platinum-based chemotherapy, the level of MDM2 expression in the tumour correlated with poor progression-free survival, which further validates the key role of MDM2 in response to platinum compounds. Our findings present a new therapeutic opportunity for patients with NSCLC, the most common form of lung cancer.
{"title":"NOTCH1 intracellular domain stabilization by MDM2 plays a major role in NSCLC response to platinum.","authors":"Sara Bernardo,Lisa Brunet,Quentin Dominique Thomas,David Bracquemond,Céline Bouclier,Marie Colomb,Maicol Mancini,Eric Fabbrizio,Alba Santos,Sylvia-Fenosoa Rasamizafy,Amina-Milissa Maacha,Anais Giry,Emilie Bousquet-Mur,Laura Papon,Marion Goussard,Christophe Fremin,Andrea Pasquier,María Rodríguez,Camille Travert,Jean-Louis Pujol,Laetitia K Linares,Lisa Heron-Milhavet,Alexandre Djiane,Irene Ferrer,Luis Paz-Ares,Xavier Quantin,Luis M Montuenga,Hélène Tourriere,Antonio Maraver","doi":"10.1038/s44321-025-00354-9","DOIUrl":"https://doi.org/10.1038/s44321-025-00354-9","url":null,"abstract":"Despite major advances in the clinical management of non-small cell lung carcinoma (NSCLC), most patients treated with first-line platinum-based chemotherapy combined with immune checkpoint inhibitors will relapse, which constitutes an unmet medical need. Here, we found that various DNA damage inducers increase the levels of Notch Intracellular Domain (NICD), the active form of NOTCH1. Mechanistically, we revealed that, upon platinum treatment, the expression levels of both MDM2 and NICD were increased and that MDM2 stabilised NICD through ubiquitination. Using NSCLC patient-derived xenografts displaying intrinsic carboplatin resistance, we demonstrated that combining carboplatin with a γ-secretase inhibitor, which hinders NICD generation, significantly improves survival and reduces tumour growth compared with carboplatin monotherapy. Furthermore, in patients with NSCLC who received platinum-based chemotherapy, the level of MDM2 expression in the tumour correlated with poor progression-free survival, which further validates the key role of MDM2 in response to platinum compounds. Our findings present a new therapeutic opportunity for patients with NSCLC, the most common form of lung cancer.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"4 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986618","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}
Pub Date : 2026-01-12DOI: 10.1038/s44321-025-00371-8
Bide Tong,Xiaoguang Zhang,Dingchao Zhu,Yulei Wang,Junyu Wei,Zixuan Ou,Huaizhen Liang,Hanpeng Xu,Zhengdong Zhang,Jie Lei,Xingyu Zhou,Di Wu,Yu Song,Kun Wang,Xiaobo Feng,Lei Tan,Zhiwei Liao,Cao Yang
Targeted protein degradation (TPD) is an emerging therapeutic approach that enables the degradation of undruggable targets via intracellular degradation systems. Extracellular vesicles (EVs) have shown potential to act as next-generation TPD platforms. However, the molecular mechanism underlying their degradation remains unknown, which restricts their application in TPD. In this study, we found that the autophagy-mediated lysosomal pathway was the major route by which EVs were degraded. MAP1LC3B recognized the LIR motifs of SQSTM1 and induced the degradation of EVs in the autophagy pathway. Based on the EV degradation mode, we developed an EV-based targeted protein degradation platform (EVTPD) using EVs loaded with the LIR motif of SQSTM1 as a degradation signal. Additionally, target protein-binding domains were integrated into the EVTPD to capture target proteins. EVTPD selectively degraded extracellular proteins without requiring receptors on target cells. Furthermore, dual-targeting EVTPD effectively degraded both TNF-α and IL-1β and exhibited potent anti-inflammatory effects in rat and goat models of intervertebral disc degeneration. This study has established a modular EV-based TPD strategy with multi-targeting potential.
{"title":"Extracellular vesicle-based targeted protein degradation platform for multiple extracellular proteins.","authors":"Bide Tong,Xiaoguang Zhang,Dingchao Zhu,Yulei Wang,Junyu Wei,Zixuan Ou,Huaizhen Liang,Hanpeng Xu,Zhengdong Zhang,Jie Lei,Xingyu Zhou,Di Wu,Yu Song,Kun Wang,Xiaobo Feng,Lei Tan,Zhiwei Liao,Cao Yang","doi":"10.1038/s44321-025-00371-8","DOIUrl":"https://doi.org/10.1038/s44321-025-00371-8","url":null,"abstract":"Targeted protein degradation (TPD) is an emerging therapeutic approach that enables the degradation of undruggable targets via intracellular degradation systems. Extracellular vesicles (EVs) have shown potential to act as next-generation TPD platforms. However, the molecular mechanism underlying their degradation remains unknown, which restricts their application in TPD. In this study, we found that the autophagy-mediated lysosomal pathway was the major route by which EVs were degraded. MAP1LC3B recognized the LIR motifs of SQSTM1 and induced the degradation of EVs in the autophagy pathway. Based on the EV degradation mode, we developed an EV-based targeted protein degradation platform (EVTPD) using EVs loaded with the LIR motif of SQSTM1 as a degradation signal. Additionally, target protein-binding domains were integrated into the EVTPD to capture target proteins. EVTPD selectively degraded extracellular proteins without requiring receptors on target cells. Furthermore, dual-targeting EVTPD effectively degraded both TNF-α and IL-1β and exhibited potent anti-inflammatory effects in rat and goat models of intervertebral disc degeneration. This study has established a modular EV-based TPD strategy with multi-targeting potential.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955967","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}
Pub Date : 2026-01-09DOI: 10.1038/s44321-025-00368-3
Juan M Lozano-Gil,Lola Rodríguez-Ruiz,Manuel Palacios,Jorge Peral,Susana Navarro,José L Fuster,Cristina Beléndez,Andrés Jérez,Laura Murillo-Sanjuán,Cristina Díaz-de-Heredia,Guzmán López-de-Hontanar,Josune Zubicaray,Julián Sevilla,Francisca Ferrer-Marín,María P Sepulcre,María L Cayuela,Diana García-Moreno,Alicia Martínez-López,Sylwia D Tyrkalska,Victoriano Mulero
Diamond-Blackfan anemia syndrome (DBAS) is marked by defective erythropoiesis caused by impaired ribosome biogenesis and aberrant signaling. Here, we investigate how ribosomal stress-induced activation of the NLRP1 inflammasome affects erythroid differentiation in DBAS. We demonstrate that FDA/EMA-approved tyrosine kinase inhibitors (TKIs) effectively mitigate defective erythropoiesis by inhibiting NLRP1 inflammasome activation. In K562 cells, nilotinib suppresses the ZAKα/P38/NLRP1/CASP1 axis, leading to increased GATA1 levels and upregulation of key erythroid genes. These effects were validated in human CD34⁺ hematopoietic stem and progenitor cells (HSPCs) and zebrafish models, where nilotinib, imatinib, and dasatinib promoted erythropoiesis while reducing caspase-1 activity. In Rps19-deficient zebrafish, RPS19-deficient human HSPCs, and HSPCs from DBAS patients, TKIs rescued erythroid differentiation and restored hemoglobin levels. Our findings highlight that targeting the NLRP1 inflammasome with TKIs may provide a novel therapeutic strategy for DBAS and other ribosomopathies.
{"title":"TKI-mediated inhibition of NLRP1 inflammasome restores erythropoiesis in DBA syndrome.","authors":"Juan M Lozano-Gil,Lola Rodríguez-Ruiz,Manuel Palacios,Jorge Peral,Susana Navarro,José L Fuster,Cristina Beléndez,Andrés Jérez,Laura Murillo-Sanjuán,Cristina Díaz-de-Heredia,Guzmán López-de-Hontanar,Josune Zubicaray,Julián Sevilla,Francisca Ferrer-Marín,María P Sepulcre,María L Cayuela,Diana García-Moreno,Alicia Martínez-López,Sylwia D Tyrkalska,Victoriano Mulero","doi":"10.1038/s44321-025-00368-3","DOIUrl":"https://doi.org/10.1038/s44321-025-00368-3","url":null,"abstract":"Diamond-Blackfan anemia syndrome (DBAS) is marked by defective erythropoiesis caused by impaired ribosome biogenesis and aberrant signaling. Here, we investigate how ribosomal stress-induced activation of the NLRP1 inflammasome affects erythroid differentiation in DBAS. We demonstrate that FDA/EMA-approved tyrosine kinase inhibitors (TKIs) effectively mitigate defective erythropoiesis by inhibiting NLRP1 inflammasome activation. In K562 cells, nilotinib suppresses the ZAKα/P38/NLRP1/CASP1 axis, leading to increased GATA1 levels and upregulation of key erythroid genes. These effects were validated in human CD34⁺ hematopoietic stem and progenitor cells (HSPCs) and zebrafish models, where nilotinib, imatinib, and dasatinib promoted erythropoiesis while reducing caspase-1 activity. In Rps19-deficient zebrafish, RPS19-deficient human HSPCs, and HSPCs from DBAS patients, TKIs rescued erythroid differentiation and restored hemoglobin levels. Our findings highlight that targeting the NLRP1 inflammasome with TKIs may provide a novel therapeutic strategy for DBAS and other ribosomopathies.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"49 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937886","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}
Pub Date : 2026-01-09DOI: 10.1038/s44321-025-00363-8
Allison T Woods,Abner A Murray,Benjamin G Vincent,Jason Akulian,Chad V Pecot
Metastatic malignant pleural effusion (MPE) represents advanced-stage cancer and is defined by the establishment of metastatic tumor foci within the pleural space. It is most commonly associated with high degrees of morbidity and mortality. Annually, over 150,000 cancer patients in the United States develop MPE, which is associated with a dismal median survival of 3-12 months. As such, efforts must be made to understand the complex biological factors driving MPE pathophysiology. In this review, we discuss what is currently known and identify knowledge gaps regarding the intrinsic MPE biology of cancer cells and the heterotypic interactions between tumor cells and the immunologic pleural ecosystem. Furthermore, we discuss the clinical opportunities of studying MPE and identify promising directions for MPE research that may lead to a deeper understanding of the disease, ultimately aiming to enhance clinical outcomes for patients with advanced cancer.
{"title":"Pathobiology and clinical significance of malignant pleural effusions.","authors":"Allison T Woods,Abner A Murray,Benjamin G Vincent,Jason Akulian,Chad V Pecot","doi":"10.1038/s44321-025-00363-8","DOIUrl":"https://doi.org/10.1038/s44321-025-00363-8","url":null,"abstract":"Metastatic malignant pleural effusion (MPE) represents advanced-stage cancer and is defined by the establishment of metastatic tumor foci within the pleural space. It is most commonly associated with high degrees of morbidity and mortality. Annually, over 150,000 cancer patients in the United States develop MPE, which is associated with a dismal median survival of 3-12 months. As such, efforts must be made to understand the complex biological factors driving MPE pathophysiology. In this review, we discuss what is currently known and identify knowledge gaps regarding the intrinsic MPE biology of cancer cells and the heterotypic interactions between tumor cells and the immunologic pleural ecosystem. Furthermore, we discuss the clinical opportunities of studying MPE and identify promising directions for MPE research that may lead to a deeper understanding of the disease, ultimately aiming to enhance clinical outcomes for patients with advanced cancer.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"29 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937885","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}
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