{"title":"Getting to the heart of cardiovascular complications associated with inflammatory arthritis.","authors":"Hong Shi, Brian H Annex","doi":"10.1038/s44321-025-00226-2","DOIUrl":"https://doi.org/10.1038/s44321-025-00226-2","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779543","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}
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":"https://doi.org/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":""},"PeriodicalIF":9.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"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":""},"PeriodicalIF":9.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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":"https://doi.org/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":""},"PeriodicalIF":9.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease.","authors":"Hongze Chen, Muhammad Azhar Nisar, Joud Mulla, Xinjian Li, Kevin Cao, Shaolei Lu, Katsuya Nagaoka, Shang Wu, Peng-Sheng Ting, Tung-Sung Tseng, Hui-Yi Lin, Xiao-Ming Yin, Wenke Feng, Zhijin Wu, Zhixiang Cheng, William Mueller, Amalia Bay, Layla Schechner, Xuewei Bai, Chiung-Kuei Huang","doi":"10.1038/s44321-025-00224-4","DOIUrl":"10.1038/s44321-025-00224-4","url":null,"abstract":"<p><p>Global hepatic DNA methylation change has been linked to human patients with metabolic dysfunction-associated steatotic liver disease (MASLD). DNA demethylation is regulated by the TET family proteins, whose enzymatic activities require 2-oxoglutarate (2-OG) and iron that both are elevated in human MASLD patients. We aimed to investigate liver TET1 in MASLD progression. Depleting TET1 using two different strategies substantially alleviated MASLD progression. Knockout (KO) of TET1 slightly improved diet induced obesity and glucose homeostasis. Intriguingly, hepatic cholesterols, triglycerides, and CD36 were significantly decreased upon TET1 depletion. Consistently, liver specific TET1 KO led to improvement of MASLD progression. Mechanistically, TET1 promoted CD36 expression through transcriptional upregulation via DNA demethylation control. Overexpression of CD36 reversed the impacts of TET1 downregulation on fatty acid uptake in hepatocytes. More importantly, targeting TET1 with a small molecule inhibitor significantly suppressed MASLD progression. Conclusively, liver TET1 plays a deleterious role in MASLD, suggesting the potential of targeting TET1 in hepatocytes to suppress MASLD.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751613","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}
Ikuan Sam, Nadine Benhamouda, Lucie Biard, Laetitia Da Meda, Kristell Desseaux, Barouyr Baroudjan, Ines Nakouri, Marion Renaud, Aurélie Sadoux, Marina Alkatrib, Jean-François Deleuze, Maxime Battistella, Yimin Shen, Matthieu Resche-Rigon, Samia Mourah, Celeste Lebbe, Eric Tartour
{"title":"Soluble CD27 differentially predicts resistance to anti-PD1 alone but not with anti-CTLA-4 in melanoma.","authors":"Ikuan Sam, Nadine Benhamouda, Lucie Biard, Laetitia Da Meda, Kristell Desseaux, Barouyr Baroudjan, Ines Nakouri, Marion Renaud, Aurélie Sadoux, Marina Alkatrib, Jean-François Deleuze, Maxime Battistella, Yimin Shen, Matthieu Resche-Rigon, Samia Mourah, Celeste Lebbe, Eric Tartour","doi":"10.1038/s44321-025-00203-9","DOIUrl":"10.1038/s44321-025-00203-9","url":null,"abstract":"<p><p>Metastatic melanoma can be treated with anti-PD-1 monotherapy or in combination with anti-CTLA-4 or anti-Lag3. However, combination therapy is associated with a high risk of toxicity. Recently, we reported that high plasma soluble CD27 (sCD27) levels reflect the intratumoral interaction of CD70-CD27 and dysfunctional T cells in the tumor microenvironment of renal cell carcinoma. In this study, we first characterized the intratumoral expression of CD70 and CD27 in melanoma tumors and their interaction in vivo. We then reported a significant association between baseline sCD27 and anti-PD-1 resistance as assessed by progression-free survival, overall survival, or 12-month complete response in two prospective cohorts of melanoma patients. Multivariate analysis confirmed that sCD27 was independently associated with clinical outcomes. Notably, sCD27 did not predict clinical response to combination therapy in either cohort. This differential predictive value of sCD27 for the two therapeutic options was later confirmed by propensity score analysis. Our results suggest that high plasma sCD27 levels predict poorer efficacy of anti-PD1 monotherapy in metastatic melanoma, justifying therapeutic escalation with a combination of anti-PD1 and anti-CTLA-4.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729358","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}
Alexandra Helleux, Guillaume Davidson, Antonin Lallement, Fatima Al Hourani, Alexandre Haller, Isabelle Michel, Anas Fadloun, Christelle Thibault-Carpentier, Xiaoping Su, Véronique Lindner, Thibault Tricard, Hervé Lang, Nizar M Tannir, Irwin Davidson, Gabriel G Malouf
{"title":"TFE3 fusions drive oxidative metabolism and ferroptosis resistance in translocation renal cell carcinoma.","authors":"Alexandra Helleux, Guillaume Davidson, Antonin Lallement, Fatima Al Hourani, Alexandre Haller, Isabelle Michel, Anas Fadloun, Christelle Thibault-Carpentier, Xiaoping Su, Véronique Lindner, Thibault Tricard, Hervé Lang, Nizar M Tannir, Irwin Davidson, Gabriel G Malouf","doi":"10.1038/s44321-025-00221-7","DOIUrl":"10.1038/s44321-025-00221-7","url":null,"abstract":"<p><p>The oncogenic mechanisms by which TFE3 fusion proteins drive translocation renal cell carcinoma (tRCC) are poorly characterized. Here, we integrated loss and gain of function experiments with multi-omics analyses in tRCC cell lines and patient tumors. High nuclear accumulation of NONO-TFE3 or PRCC-TFE3 fusion proteins promotes their broad binding across the genome at H3K27ac-marked active chromatin, engaging a core set of M/E-box-containing regulatory elements to activate specific gene expression programs as well as promiscuous binding to active promoters to stimulate mRNA synthesis. Within the core program, TFE3 fusions directly regulate genes involved in ferroptosis resistance and oxidative phosphorylation metabolism (OxPhos). Consequently, human tRCC tumors display high OxPhos scores that persist during their epithelial to mesenchymal transition (EMT). We further show that tRCC tumor aggressiveness is related to their EMT and their associated enrichment in myofibroblast cancer-associated fibroblasts (myCAFs) that are both hallmarks of poor prognostic outcomes. We define tRCC as a novel metabolic subtype of renal cancer and provide unique insights into how broad genomic binding of TFE3 fusion proteins regulates OxPhos and ferroptosis resistance.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729359","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}
{"title":"Beyond mitotic arrest: the diverse effects of microtubule-targeting drugs on tumor vasculature.","authors":"April L Risinger","doi":"10.1038/s44321-025-00223-5","DOIUrl":"https://doi.org/10.1038/s44321-025-00223-5","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718118","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}
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":""},"PeriodicalIF":9.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
