{"title":"Targeting HPK1 inhibits neutrophil responses to mitigate post-stroke lung and cerebral injuries.","authors":"Tingting Zhang, Ying Sun, Jing Xia, Hongye Fan, Dingfang Shi, Qian Wu, Ming Huang, Xiao-Yu Hou","doi":"10.1038/s44321-025-00220-8","DOIUrl":"10.1038/s44321-025-00220-8","url":null,"abstract":"<p><p>Circulating neutrophils are responsible for poor neurological outcomes and have been implicated in respiratory morbidity after acute ischemic stroke (AIS). However, the molecular mechanisms regulating neutrophil responses and their pathological relevance in post-stroke complications remain unclear. In this study, we investigated the involvement of hematopoietic progenitor kinase 1 (HPK1) in neutrophil responses and mobilization, as well as subsequent lung and cerebral injuries following AIS. We found that lipopolysaccharide treatment triggered neutrophil activation in an HPK1-dependent manner. HPK1 enhanced intrinsic NF-κB/STAT3/p38-MAPK pathways and gasdermin D cleavage, leading to neutrophil hyperactivation. Following AIS, HPK1 promoted the mobilization of CXCR2<sup>high</sup> bone marrow neutrophils. HPK1 loss inhibited peripheral neutrophil hyperactivation, neutrophil infiltration, and aggregation of neutrophil extracellular traps, progressively alleviating systemic inflammation and impairments in mouse pulmonary and neurological functions. Furthermore, HPK1 pharmacological inhibition attenuated post-stroke pulmonary and neurological impairments in mice. Our findings revealed that HPK1 upregulates neutrophil mobilization and various responses, promoting post-stroke systemic inflammation and tissue injury. This study highlights HPK1 as a therapeutic target for improving pulmonary and neurological functions after AIS.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1018-1040"},"PeriodicalIF":9.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763110","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}
{"title":"Identification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity.","authors":"Yi-Cheng Chang, Meng-Lun Hsieh, Hsiao-Lin Lee, Siow-Wey Hee, Chi-Fon Chang, Hsin-Yung Yen, Yi-An Chen, Yet-Ran Chen, Ya-Wen Chou, Fu-An Li, Yi-Yu Ke, Shih-Yi Chen, Ming-Shiu Hung, Alfur Fu-Hsin Hung, Jing-Yong Huang, Chu-Hsuan Chiu, Shih-Yao Lin, Sheue-Fang Shih, Chih-Neng Hsu, Juey-Jen Hwang, Teng-Kuang Yeh, Ting-Jen Rachel Cheng, Karen Chia-Wen Liao, Daniel Laio, Shu-Wha Lin, Tzu-Yu Chen, Chun-Mei Hu, Ulla Vogel, Daniel Saar, Birthe B Kragelund, Lun Kelvin Tsou, Yu-Hua Tseng, Lee-Ming Chuang","doi":"10.1038/s44321-025-00216-4","DOIUrl":"10.1038/s44321-025-00216-4","url":null,"abstract":"<p><p>Peroxisome proliferator-activated receptor γ (PPARγ) is a master transcriptional regulator of systemic insulin sensitivity and energy balance. The anti-diabetic drug thiazolidinediones (TZDs) are potent synthetic PPARγ ligands with undesirable side effects, including obesity, fluid retention, and osteoporosis. 15-keto prostaglandin E2 (15-keto-PGE2) is an endogenous PPARγ ligand metabolized by prostaglandin reductase 2 (PTGR2). Here, we confirmed that 15-keto-PGE2 binds to and activates PPARγ via covalent binding. In patients with type 2 diabetes and obese mice, serum 15-keto-PGE2 levels were decreased. Administration of 15-keto-PGE2 improves glucose homeostasis and prevented diet-induced obesity in mice. Either genetic inhibition of PTGR2 or PTGR2 inhibitor BPRPT0245 protected mice from diet-induced obesity, insulin resistance, and hepatic steatosis without causing fluid retention and osteoporosis. In conclusion, inhibition of PTGR2 is a new therapeutic approach to treat diabetes and obesity through increasing endogenous PPARγ ligands while avoiding side effects including increased adiposity, fluid retention, and osteoporosis.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"938-966"},"PeriodicalIF":9.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676982","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}
EMBO Molecular MedicinePub Date : 2025-05-01Epub Date: 2025-03-21DOI: 10.1038/s44321-025-00215-5
Marey Messingschlager, Sebastian D Mackowiak, Maria Theresa Voelker, Matthias Bieg, Jennifer Loske, Robert Lorenz Chua, Johannes Liebig, Sören Lukassen, Loreen Thürmann, Anke Seegebarth, Sven Twardziok, Daria Doncevic, Carl Herrmann, Stephan Lorenz, Sven Klages, Fridolin Steinbeis, Martin Witzenrath, Florian Kurth, Christian Conrad, Leif E Sander, Naveed Ishaque, Roland Eils, Irina Lehmann, Sven Laudi, Saskia Trump
{"title":"DNA methylation changes during acute COVID-19 are associated with long-term transcriptional dysregulation in patients' airway epithelial cells.","authors":"Marey Messingschlager, Sebastian D Mackowiak, Maria Theresa Voelker, Matthias Bieg, Jennifer Loske, Robert Lorenz Chua, Johannes Liebig, Sören Lukassen, Loreen Thürmann, Anke Seegebarth, Sven Twardziok, Daria Doncevic, Carl Herrmann, Stephan Lorenz, Sven Klages, Fridolin Steinbeis, Martin Witzenrath, Florian Kurth, Christian Conrad, Leif E Sander, Naveed Ishaque, Roland Eils, Irina Lehmann, Sven Laudi, Saskia Trump","doi":"10.1038/s44321-025-00215-5","DOIUrl":"10.1038/s44321-025-00215-5","url":null,"abstract":"<p><p>Molecular changes underlying the persistent health effects after SARS-CoV-2 infection remain poorly understood. To discern the gene regulatory landscape in the upper respiratory tract of COVID-19 patients, we performed enzymatic DNA methylome and single-cell RNA sequencing in nasal cells of COVID-19 patients (n = 19, scRNA-seq n = 14) and controls (n = 14, scRNA-seq n = 10). In addition, we resampled a subset of these patients for transcriptome analyses at 3 (n = 7) and 12 months (n = 5) post infection and followed the expression of differentially regulated genes over time. Genome-wide DNA methylation analysis revealed 3112 differentially methylated regions between COVID-19 patients and controls. Hypomethylated regions affected immune regulatory genes, while hypermethylated regions were associated with genes governing ciliary function. These genes were not only downregulated in the acute phase of the disease but sustained repressed up to 12 months post infection in ciliated cells. Validation in an independent cohort collected 6 months post infection (n = 15) indicated symptom-dependent transcriptional repression of ciliary genes. We therefore propose that hypermethylation observed in the acute phase may exert a long-term effect on gene expression, possibly contributing to post-acute COVID-19 sequelae.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"923-937"},"PeriodicalIF":9.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676977","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}
EMBO Molecular MedicinePub Date : 2025-05-01Epub Date: 2025-04-03DOI: 10.1038/s44321-025-00227-1
Andreas Margraf, Jianmin Chen, Marilena Christoforou, Pol Claria-Ribas, Ayda Henriques Schneider, Chiara Cecconello, Weifeng Bu, Paul R C Imbert, Thomas D Wright, Stefan Russo, Isobel A Blacksell, Duco S Koenis, Jesmond Dalli, John A Lupisella, Nicholas R Wurtz, Ricardo A Garcia, Dianne Cooper, Lucy V Norling, Mauro Perretti
{"title":"Formyl-peptide receptor type 2 activation mitigates heart and lung damage in inflammatory arthritis.","authors":"Andreas Margraf, Jianmin Chen, Marilena Christoforou, Pol Claria-Ribas, Ayda Henriques Schneider, Chiara Cecconello, Weifeng Bu, Paul R C Imbert, Thomas D Wright, Stefan Russo, Isobel A Blacksell, Duco S Koenis, Jesmond Dalli, John A Lupisella, Nicholas R Wurtz, Ricardo A Garcia, Dianne Cooper, Lucy V Norling, Mauro Perretti","doi":"10.1038/s44321-025-00227-1","DOIUrl":"10.1038/s44321-025-00227-1","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is associated with heart and lung dysfunction. Current therapies fail to attenuate such complications. Here, we identify formyl-peptide receptor type 2 (FPR2) as a therapeutic target to treat heart and lung dysfunction associated with inflammatory arthritis. Arthritic mice on high levels of dietary homocysteine develop cardiac diastolic dysfunction and reduced lung compliance, mirroring two comorbidities in RA. Therapeutic administration of a small molecule FPR2 agonist (BMS986235) to hyper-homocysteine arthritic mice prevented diastolic dysfunction (monitored by echocardiography) and restored lung compliance. These tissue-specific effects were secondary to reduced neutrophil infiltration, modulation of fibroblast activation and phenotype (in the heart) and attenuation of monocyte and macrophage numbers (in the lung). A dual FPR1/2 agonist (compound 43) failed to prevent the reduction in lung compliance of arthritic mice and promoted the accumulation of inflammatory monocytes and pro-fibrotic macrophages in lung parenchyma. This cellular response lies downstream of FPR1-mediated potentiation of CCL2-dependent monocyte chemotaxis and activation. This finding supports the therapeutic development of selective FPR2 agonists to mitigate two impactful comorbidities associated with inflammatory arthritides.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1153-1183"},"PeriodicalIF":9.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779541","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}
EMBO Molecular MedicinePub Date : 2025-05-01Epub Date: 2025-04-01DOI: 10.1038/s44321-025-00219-1
Rubén de Dios, Kavita Gadar, Chris R Proctor, Evgenia Maslova, Jie Han, Mohamed A N Soliman, Dominika Krawiel, Emma L Dunbar, Bhupender Singh, Stelinda Peros, Tom Killelea, Anna-Luisa Warnke, Marius M Haugland, Edward L Bolt, Christian S Lentz, Christian J Rudolph, Ronan R McCarthy
{"title":"Saccharin disrupts bacterial cell envelope stability and interferes with DNA replication dynamics.","authors":"Rubén de Dios, Kavita Gadar, Chris R Proctor, Evgenia Maslova, Jie Han, Mohamed A N Soliman, Dominika Krawiel, Emma L Dunbar, Bhupender Singh, Stelinda Peros, Tom Killelea, Anna-Luisa Warnke, Marius M Haugland, Edward L Bolt, Christian S Lentz, Christian J Rudolph, Ronan R McCarthy","doi":"10.1038/s44321-025-00219-1","DOIUrl":"10.1038/s44321-025-00219-1","url":null,"abstract":"<p><p>Saccharin has been part of the human diet for over 100 years, and there is a comprehensive body of evidence demonstrating that it can influence the gut microbiome, ultimately impacting human health. However, the precise mechanisms through which saccharin can impact bacteria have remained elusive. In this work, we demonstrate that saccharin inhibits cell division, leading to cell filamentation with altered DNA synthesis dynamics. We show that these effects on the cell are superseded by the formation of bulges emerging from the cell envelope, which ultimately trigger cell lysis. We demonstrate that saccharin can inhibit the growth of both Gram-negative and Gram-positive bacteria as well as disrupt key phenotypes linked to host colonisation, such as motility and biofilm formation. In addition, we test its potential to disrupt established biofilms (single-species as well as polymicrobial) and its capacity to re-sensitise multidrug-resistant pathogens to last-resort antibiotics. Finally, we present in vitro and ex vivo evidence of the versatility of saccharin as a potential antimicrobial by integrating it into an effective hydrogel wound dressing.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"993-1017"},"PeriodicalIF":9.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763464","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}
{"title":"Modulating CCTG repeat expansion toxicity in DM2 Drosophila model through TDP1 inhibition.","authors":"Yingbao Zhu, Shengwei Xiao, Xinxin Guan, Haitao Deng, Liqiang Ai, Kaijing Fan, Jin Xue, Guangxu Li, Xiaoxue Bi, Qiao Xiao, Yuanjiang Huang, Lin Jiang, Wen Huang, Peng Jin, Ranhui Duan","doi":"10.1038/s44321-025-00217-3","DOIUrl":"10.1038/s44321-025-00217-3","url":null,"abstract":"<p><p>Myotonic dystrophy type 2 (DM2), caused by CCTG repeat expansion, is a common adult-onset disorder characterized by myotonia and progressive muscle degeneration with no effective treatment. Here, we identified Tyrosyl-DNA phosphodiesterase 1 (TDP1) as a novel modifier for DM2 therapeutic intervention through a high-throughput chemical screening of 2160 compounds. Moreover, we detailed how both genetic and pharmacological inhibition of TDP1 translates to a cascade of beneficial effects, including improved motor functions, amelioration of progressive muscle degeneration, repair of muscle fiber damage, and normalization of aberrant molecular pathology. Remarkably, the TDP1 inhibition led to substantial CCTG repeat contractions, a mechanism that underlies the observed muscle toxicity and neurodegeneration. Our results highlighted the potential of TDP1 as a molecular target for addressing the complex interplay between repeat expansions and neuromuscular degeneration in DM2, hinting at broader applicability in a spectrum of repeat expansion disorders.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"967-992"},"PeriodicalIF":9.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709135","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}
EMBO Molecular MedicinePub Date : 2025-05-01Epub Date: 2025-03-26DOI: 10.1038/s44321-025-00222-6
Bo He, Kira H Wood, Zhi-Jie Li, Judith A Ermer, Ji Li, Edward R Bastow, Suraj Sakaram, Phillip K Darcy, Lisa J Spalding, Cameron T Redfern, Jordi Canes, Mafalda Oliveira, Aleix Prat, Javier Cortes, Erik W Thompson, Bruce A Littlefield, Andrew Redfern, Ruth Ganss
{"title":"Selective tubulin-binding drugs induce pericyte phenotype switching and anti-cancer immunity.","authors":"Bo He, Kira H Wood, Zhi-Jie Li, Judith A Ermer, Ji Li, Edward R Bastow, Suraj Sakaram, Phillip K Darcy, Lisa J Spalding, Cameron T Redfern, Jordi Canes, Mafalda Oliveira, Aleix Prat, Javier Cortes, Erik W Thompson, Bruce A Littlefield, Andrew Redfern, Ruth Ganss","doi":"10.1038/s44321-025-00222-6","DOIUrl":"10.1038/s44321-025-00222-6","url":null,"abstract":"<p><p>The intratumoral immune milieu is crucial for the success of anti-cancer immunotherapy. We show here that stromal modulation by the tubulin-binding anti-cancer drugs combretastatin A4 (CA-4) and eribulin improved tumor perfusion and anti-tumor immunity. This was achieved by reverting highly proliferative, angiogenic pericytes into a quiescent, contractile state which durably normalized the vascular bed and reduced hypoxia in mouse models of pancreatic neuroendocrine cancer, breast cancer and melanoma. The crucial event in pericyte phenotype switching was RhoA kinase activation, which distinguished CA-4 and eribulin effects from other anti-mitotic drugs such as paclitaxel and vinorelbine. Importantly, eribulin pre-treatment sensitized tumors for adoptive T cell therapy or checkpoint inhibition resulting in effector cell infiltration and better survival outcomes in mice. In breast cancer patients, eribulin neoadjuvant treatment induced pericyte maturity and RhoA kinase activity indicating similar vessel remodeling effects as seen in mice. Moreover, a contractile pericyte signature was associated with overall better survival outcome in two independent breast cancer cohorts. This underscores the potential of re-purposing specific anti-cancer drugs to enable synergistic complementation with emerging immunotherapies.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1071-1100"},"PeriodicalIF":9.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718058","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}
Sara Lucchini,James G Nicholson,Xinyu Zhang,Jacob Househam,Yau Mun Lim,Maximilian Mossner,Thomas O Millner,Sebastian Brandner,Trevor Graham,Silvia Marino
{"title":"A novel model of glioblastoma recurrence to identify therapeutic vulnerabilities.","authors":"Sara Lucchini,James G Nicholson,Xinyu Zhang,Jacob Househam,Yau Mun Lim,Maximilian Mossner,Thomas O Millner,Sebastian Brandner,Trevor Graham,Silvia Marino","doi":"10.1038/s44321-025-00237-z","DOIUrl":"https://doi.org/10.1038/s44321-025-00237-z","url":null,"abstract":"Glioblastoma remains incurable and recurs in all patients. Here we design and characterize a novel induced-recurrence model in which mice xenografted with primary patient-derived glioma initiating/stem cells (GIC) are treated with a therapeutic regimen closely recapitulating patient standard of care, followed by monitoring until tumours recur (induced recurrence patient-derived xenografts, IR-PDX). By tracking in vivo tumour growth, we confirm the patient specificity and initial efficacy of treatment prior to recurrence. Availability of longitudinally matched pairs of primary and recurrent GIC enabled patient-specific evaluation of the fidelity with which the model recapitulated phenotypes associated with the true recurrence. Through comprehensive multi-omic analyses, we show that the IR-PDX model recapitulates aspects of genomic, epigenetic, and transcriptional state heterogeneity upon recurrence in a patient-specific manner. The accuracy of the IR-PDX enabled both novel biological insights, including the positive association between glioblastoma recurrence and levels of ciliated neural stem cell-like tumour cells, and the identification of druggable patient-specific therapeutic vulnerabilities. This proof-of-concept study opens the possibility for prospective precision medicine approaches to identify target-drug candidates for treatment at glioblastoma recurrence.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"9 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889272","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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