Hyun-Ju Cho,Joy Smith,Christopher H Switzer,Eleni Louka,Rebecca L Charles,Oleksandra Prysyazhna,Ewald Schroder,Mariana Fernandez-Caggiano,Daniel Simoes de Jesus,Seda Eminaga,Xiaoke Yin,Xiaoping Yang,Steven Lynham,Manuel Mayr,Valle Morales,Katiuscia Bianchi,Vinothini Rajeeve,Pedro R Cutillas,Adam J Mead,Philip Eaton
{"title":"SFX-01 is therapeutic against myeloproliferative disorders caused by activating mutations in Shp2.","authors":"Hyun-Ju Cho,Joy Smith,Christopher H Switzer,Eleni Louka,Rebecca L Charles,Oleksandra Prysyazhna,Ewald Schroder,Mariana Fernandez-Caggiano,Daniel Simoes de Jesus,Seda Eminaga,Xiaoke Yin,Xiaoping Yang,Steven Lynham,Manuel Mayr,Valle Morales,Katiuscia Bianchi,Vinothini Rajeeve,Pedro R Cutillas,Adam J Mead,Philip Eaton","doi":"10.1038/s44321-025-00267-7","DOIUrl":"https://doi.org/10.1038/s44321-025-00267-7","url":null,"abstract":"Activating mutations of Src homology-2 domain-containing protein tyrosine phosphatase-2 (Shp2) cause multiple childhood conditions for which there is an unmet therapeutic need, including juvenile myelomonocytic leukemia (JMML) and Noonan syndrome. SFX-01, an α-cyclodextrin-stabilized sulforaphane complex currently in clinical development, covalently adducts cysteine residues. Using unbiased proteomics, its protein targets were identified, including Shp2. SFX-01 induced an inhibitory dithiolethione modification at the Shp2 active site cysteine. Importantly, in a transgenic mouse model of human Noonan syndrome with hyperactive D61G Shp2, SFX-01 concomitantly normalized their phosphatase activity and myeloid cell count. Furthermore, SFX-01 also attenuated JMML human patient-derived hematopoietic stem cell proliferation that was linked to STAT1 signaling and decreased cyclin D1 expression, resulting in cell-cycle arrest. We conclude that SFX-01 is an activating mutant Shp2 inhibitor and may offer beneficial effects in patients with JMML or Noonan syndrome.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"12 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603985","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}
Jie Zhou, Dong Wang, Bosco Ho-Yin Wong, Cun Li, Vincent Kwok-Man Poon, Lei Wen, Xiaoyu Zhao, Man Chun Chiu, Xiaojuan Liu, Ziwei Ye, Shuofeng Yuan, Kong-Hung Sze, Jasper Fuk-Woo Chan, Hin Chu, Kelvin Kai-Wang To, Kwok Yung Yuen
{"title":"Author Correction: Identification and characterization of GLDC as host susceptibility gene to severe influenza.","authors":"Jie Zhou, Dong Wang, Bosco Ho-Yin Wong, Cun Li, Vincent Kwok-Man Poon, Lei Wen, Xiaoyu Zhao, Man Chun Chiu, Xiaojuan Liu, Ziwei Ye, Shuofeng Yuan, Kong-Hung Sze, Jasper Fuk-Woo Chan, Hin Chu, Kelvin Kai-Wang To, Kwok Yung Yuen","doi":"10.1038/s44321-024-00164-5","DOIUrl":"https://doi.org/10.1038/s44321-024-00164-5","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599737","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}
France Côté, Elizabeth Prairie, Estefania Marin Sierra, Christiane Quiniou, Tiffany Habelrih, Wendy Xu, Béatrice Ferri, Xin Hou, Isabelle Lahaie, Nadia Côté, Sarah-Eve Loiselle, Laurence Gobeil, Kevin Sawaya, Aurélie Faucher, Amélie Beaulieu, Sandrine Delisle, Marie-Pénélope Simard, Mohammad Ali Mohammad Nezhady, Véronique Laplante, Allan Reuben, Sidi Mohamed Kalaidji, Emmanuel Bajon, Gael Cagnone, Kelycia B Leimert, Jean-François Gauchat, Luc Gaudreau, Sarah Robertson, William D Lubell, David M Olson, Sylvain Chemtob
{"title":"A novel modulator of IL-6R prevents inflammation-induced preterm birth and improves newborn outcome.","authors":"France Côté, Elizabeth Prairie, Estefania Marin Sierra, Christiane Quiniou, Tiffany Habelrih, Wendy Xu, Béatrice Ferri, Xin Hou, Isabelle Lahaie, Nadia Côté, Sarah-Eve Loiselle, Laurence Gobeil, Kevin Sawaya, Aurélie Faucher, Amélie Beaulieu, Sandrine Delisle, Marie-Pénélope Simard, Mohammad Ali Mohammad Nezhady, Véronique Laplante, Allan Reuben, Sidi Mohamed Kalaidji, Emmanuel Bajon, Gael Cagnone, Kelycia B Leimert, Jean-François Gauchat, Luc Gaudreau, Sarah Robertson, William D Lubell, David M Olson, Sylvain Chemtob","doi":"10.1038/s44321-025-00257-9","DOIUrl":"https://doi.org/10.1038/s44321-025-00257-9","url":null,"abstract":"<p><p>Preterm birth (PTB) is a major cause of neonatal mortality and morbidity. Evidence supports a determinant role for interleukin-6 (IL-6) in the pathophysiology of PTB. Our group developed a small peptide, HSJ633, that antagonizes the interleukin-6 receptor (IL-6R). Binding assays performed on HEK-Blue IL-6 cells reveal that HSJ633 appears to bind to IL-6R on a site remote from the IL-6 binding domain. Concordantly, HSJ633 selectively inhibits STAT3 phosphorylation while preserving the activation of cytoprotective AKT, p38, and ERK 1/2. In vivo, in a murine model of LPS-induced PTB, HSJ633 reduces inflammation in gestational and fetal tissues, preserves the integrity of fetal organs, and improves the survival of neonatal progeny when administered before and after the induction of labor by an inflammatory stimulus. Relevantly, the pharmacological inhibition of STAT3 in mice is sufficient to prevent PTB. Findings reveal first-in-class efficacy of a small peptide inhibitor of IL-6R, namely HSJ633, in impeding the inflammatory cascade associated with PTB and mitigating adverse neonatal outcomes.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559521","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}
EMBO Molecular MedicinePub Date : 2025-07-01Epub Date: 2025-06-05DOI: 10.1038/s44321-025-00255-x
Ildefonso Sánchez-Cerrillo, María Agudo-Lera, Olga Popova, Ilya Tsukalov, Marta Calvet-Mirabent, Ignacio de Los Santos, Lucio García-Fraile, Patricia Fuentes, Cristina Delgado-Arévalo, Juan Alcain, Nerea Sánchez-Gaona, Judith Grau-Expósito, María Lázaro-Díez, Cecilia Muñoz-Calleja, Arantzazu Alfranca, Meritxell Genescà, Julia G Prado, Vladimir Vrbanac, Alejandro Balazs, María José Buzón, María L Toribio, María A Muñoz-Fernández, Francisco Sánchez-Madrid, Enrique Martín-Gayo
{"title":"Combined dendritic cell and anti-TIGIT immunotherapy potentiates adaptive NK cells against HIV-1.","authors":"Ildefonso Sánchez-Cerrillo, María Agudo-Lera, Olga Popova, Ilya Tsukalov, Marta Calvet-Mirabent, Ignacio de Los Santos, Lucio García-Fraile, Patricia Fuentes, Cristina Delgado-Arévalo, Juan Alcain, Nerea Sánchez-Gaona, Judith Grau-Expósito, María Lázaro-Díez, Cecilia Muñoz-Calleja, Arantzazu Alfranca, Meritxell Genescà, Julia G Prado, Vladimir Vrbanac, Alejandro Balazs, María José Buzón, María L Toribio, María A Muñoz-Fernández, Francisco Sánchez-Madrid, Enrique Martín-Gayo","doi":"10.1038/s44321-025-00255-x","DOIUrl":"10.1038/s44321-025-00255-x","url":null,"abstract":"<p><p>Natural Killer (NK) cells are promising candidates for targeting persistently infected CD4 + T cells in people with HIV-1 (PWH). However, chronicity of HIV-1 infection impairs NK cell functionality, requiring additional strategies to potentiate their cytotoxic activity. This study demonstrates that dendritic cells primed with nanoparticles containing Poly I:C (Nano-PIC-MDDC) enhance the natural cytotoxic function of NK cells from effective responder PWH. These NK cells exhibit increased proportions of NKG2C+ cell subsets capable of eliminating HIV-1 infected CD4 + T cells through the TRAIL receptor. In contrast, in non-responder PWH, elevated expression of the inhibitory receptor TIGIT is associated with reduced frequencies of NKG2C + NK cells and diminished TRAIL expression. TIGIT blockade restores cytotoxicity of NK cells from non-responder PWH against HIV-1-infected cells by upregulating TRAIL. Furthermore, combining Nano-PIC-MDDC-primed NK cells with anti-TIGIT immunotherapy in humanized NSG mice reduces the expansion of HIV-1 infected cells, preserves NKG2C + NK cell precursors and increases TRAIL expression in tissue. Collectively, these findings support the combined use of Nano-PIC-MDDC and TIGIT blockade as a promising immunotherapeutic strategy toward an HIV-1 cure.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1756-1793"},"PeriodicalIF":9.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233536","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 : 2025-07-01Epub Date: 2025-06-20DOI: 10.1038/s44321-025-00258-8
Sjoerd Viktor Beentjes, Artur Miralles Méharon, Julia Kaczmarczyk, Amanda Cassar, Gemma Louise Samms, Nima S Hejazi, Ava Khamseh, Chris P Ponting
{"title":"Replicated blood-based biomarkers for myalgic encephalomyelitis not explicable by inactivity.","authors":"Sjoerd Viktor Beentjes, Artur Miralles Méharon, Julia Kaczmarczyk, Amanda Cassar, Gemma Louise Samms, Nima S Hejazi, Ava Khamseh, Chris P Ponting","doi":"10.1038/s44321-025-00258-8","DOIUrl":"10.1038/s44321-025-00258-8","url":null,"abstract":"<p><p>Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a common female-biased disease. ME/CFS diagnosis is hindered by the absence of biomarkers that are unaffected by patients' low physical activity level. Our analysis used semi-parametric efficient estimators, an initial Super Learner fit followed by a one-step correction, three mediators, and natural direct and indirect estimands, to decompose the average effect of ME/CFS status on molecular and cellular traits. For this, we used UK Biobank data for up to 1455 ME/CFS cases and 131,303 controls. Hundreds of traits differed significantly between cases and controls, including 116 significant for both female and male cohorts. These were indicative of chronic inflammation, insulin resistance and liver disease. Nine of 14 traits were replicated in the smaller All-of-Us cohort. Results cannot be explained by restricted activity: via an activity mediator, ME/CFS status significantly affected only 1 of 3237 traits. Individuals with post-exertional malaise show stronger biomarker differences. Single traits could not cleanly distinguish cases from controls. Nevertheless, these results keep alive the future ambition of a blood-based biomarker panel for accurate ME/CFS diagnosis.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1868-1891"},"PeriodicalIF":9.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332652","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 : 2025-07-01Epub Date: 2025-06-10DOI: 10.1038/s44321-025-00256-w
Tiantian Xu, Liang Zhong, Qianxi Liu, Fei Wang, Wenjing Kuang, Jiaqi Liang, Dan Yang, Xikun Zhou, Hongxia Dan, Hang Zhao, Taiwen Li, Xin Zeng, Jing Li, Qianming Chen
{"title":"NRF2 modulates WNT signaling pathway to enhance photodynamic therapy resistance in oral leukoplakia.","authors":"Tiantian Xu, Liang Zhong, Qianxi Liu, Fei Wang, Wenjing Kuang, Jiaqi Liang, Dan Yang, Xikun Zhou, Hongxia Dan, Hang Zhao, Taiwen Li, Xin Zeng, Jing Li, Qianming Chen","doi":"10.1038/s44321-025-00256-w","DOIUrl":"10.1038/s44321-025-00256-w","url":null,"abstract":"<p><p>Oral leukoplakia (OLK) is a common potentially malignant oral disorder with high risk of malignant transformation. While photodynamic therapy (PDT) offers a minimally invasive treatment for OLK, some patients show resistance to PDT and the mechanisms remain unclear. This study aims to identify key regulatory pathways driving PDT resistance in OLK. Single-cell RNA sequencing of OLK samples (three PDT-sensitive, three PDT-resistant) revealed significant NRF2 upregulation in resistant tissues. Validation across two independent cohorts (n = 117) confirmed that p-NRF2 levels were significantly elevated in PDT-resistant cases, exhibiting strong predictive power for treatment response (AUC > 0.8). Mechanistically, NRF2 promotes CTNNB1 transcription, activates WNT signaling, modulates reactive oxygen species responses, and regulates keratinization, collectively contributing to PDT resistance. In a 4NQO-induced OLK mouse model, NRF2 inhibition combined with PDT effectively reversed OLK lesions and restored mucosal histology. These findings establish p-NRF2 as a valuable biomarker for guiding PDT regimens in OLK patients, reveal NRF2's role in mediating PDT resistance via the WNT signaling pathway, and highlight NRF2 inhibition as a promising strategy to enhance PDT efficacy.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1794-1824"},"PeriodicalIF":9.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265719","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 : 2025-07-01Epub Date: 2025-05-27DOI: 10.1038/s44321-025-00253-z
Ericka C M Itang, Vincent Albrecht, Alicia-Sophie Schebesta, Marvin Thielert, Anna-Lisa Lanz, Katharina Danhauser, Jessica Jin, Tobias Prell, Sophie Strobel, Christoph Klein, Matthias Mann, Susanne Pangratz-Fuehrer, Johannes Mueller-Reif
{"title":"Ontology-guided clustering enables proteomic analysis of rare pediatric disorders.","authors":"Ericka C M Itang, Vincent Albrecht, Alicia-Sophie Schebesta, Marvin Thielert, Anna-Lisa Lanz, Katharina Danhauser, Jessica Jin, Tobias Prell, Sophie Strobel, Christoph Klein, Matthias Mann, Susanne Pangratz-Fuehrer, Johannes Mueller-Reif","doi":"10.1038/s44321-025-00253-z","DOIUrl":"10.1038/s44321-025-00253-z","url":null,"abstract":"<p><p>The study of rare pediatric disorders is fundamentally limited by small patient numbers, making it challenging to draw meaningful biological conclusions. To address this, we developed a framework integrating clinical ontologies with proteomic profiling, enabling the systematic analysis of rare conditions in aggregate. We applied this approach to urine and plasma samples from 1140 children and adolescents, encompassing 394 distinct disease conditions and healthy controls. Using advanced mass spectrometry workflows, we quantified over 5000 proteins in urine, 900 in undepleted (neat) plasma, and 1900 in perchloric acid-depleted plasma. Embedding SNOMED CT clinical terminology in a network structure allowed us to group rare conditions based on their clinical relationships, enabling statistical analysis even for diseases with as few as two patients. This approach revealed molecular signatures across developmental stages and disease clusters while accounting for age- and sex-specific variation. Our framework provides a generalizable solution for studying heterogeneous patient populations where traditional case-control studies are impractical, bridging the gap between clinical classification and molecular profiling of rare diseases.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1842-1867"},"PeriodicalIF":9.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157329","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 : 2025-07-01Epub Date: 2025-05-30DOI: 10.1038/s44321-025-00245-z
Julia Hecker, Christina Plattner, Camila A Cancino, Britt-Sabina Löscher, Judith Saurenbach, Marilena Letizia, Dietmar Rieder, Inka Freise, Kristina Koop, Clemens Neufert, Désirée Kunkel, Zainab Al Khatim, Lars-Arne Schaafs, Anja Schütz, Christoph Becker, Raja Atreya, Zlatko Trajanoski, Andre Franke, Elena Sonnenberg, Ahmed N Hegazy, Britta Siegmund, Carl Weidinger
{"title":"IL-36 signaling as a drug target in Crohn's disease patients with IL36RN mutations.","authors":"Julia Hecker, Christina Plattner, Camila A Cancino, Britt-Sabina Löscher, Judith Saurenbach, Marilena Letizia, Dietmar Rieder, Inka Freise, Kristina Koop, Clemens Neufert, Désirée Kunkel, Zainab Al Khatim, Lars-Arne Schaafs, Anja Schütz, Christoph Becker, Raja Atreya, Zlatko Trajanoski, Andre Franke, Elena Sonnenberg, Ahmed N Hegazy, Britta Siegmund, Carl Weidinger","doi":"10.1038/s44321-025-00245-z","DOIUrl":"10.1038/s44321-025-00245-z","url":null,"abstract":"<p><p>The IL-36 signaling pathway has recently been identified as a key regulator of intestinal homeostasis and inflammation. However, the role of mutations in the IL-36R signaling pathway in the pathogenesis of inflammatory bowel disease remains unclear. We here identified four Crohn's disease patients with heterozygous missense mutations in the IL-36 receptor antagonist (IL36RN, IL-36RA). Experimental overexpression and functional assays demonstrated that two identified mutations resulted in reduced expression of IL-36RA. In-depth immune profiling of one IL36RN-mutated patient revealed an increased response of PBMCs to IL-36 stimulation and elevated serum levels of IL-36-regulated cytokines. Administration of the IL-36R-blocking antibody spesolimab to this patient resulted in a reduction of intestinal inflammation and alterations in immune cell composition and function. Our findings indicate that pathogenic IL36RN mutations may contribute to the pathogenesis of Crohn's disease in a subset of patients and that inhibiting IL-36 signaling could offer a personalized therapeutic approach for these patients.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1539-1555"},"PeriodicalIF":9.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186806","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 : 2025-07-01Epub Date: 2025-06-04DOI: 10.1038/s44321-025-00259-7
Jiyan Yu, Chunhe Yang, Xintao Zhu, Zhankun Wang, Boping Xu, Ye Cai, Jingbo Zhao, Ruijian Guo, Wuzhou Yuan, Jianqing Wang, Bohao Dong, Frank Ron Zheng, Shuang Yang
{"title":"A DNA alteration and methylation co-detection method for clinical purpose.","authors":"Jiyan Yu, Chunhe Yang, Xintao Zhu, Zhankun Wang, Boping Xu, Ye Cai, Jingbo Zhao, Ruijian Guo, Wuzhou Yuan, Jianqing Wang, Bohao Dong, Frank Ron Zheng, Shuang Yang","doi":"10.1038/s44321-025-00259-7","DOIUrl":"10.1038/s44321-025-00259-7","url":null,"abstract":"<p><p>Traditional approaches for capturing genomic alterations and DNA methylation require separate assays, complicating clinical workflows and limiting sample utilization, particularly with low-input materials like cell-free DNA. To address these challenges, we introduce a streamlined approach combining mutation and methylation profiling via mutation-protective strand synthesis with modified deoxycytidine triphosphates, demonstrating high concordance with standard enzymatic methyl-seq and DNA-seq in both whole-genome sequencing of cell lines and targeted sequencing of clinical samples. In potential clinical contexts, incorporating multi-omics information with this approach modestly improve circulating tumor DNA (ctDNA) detection by ~12% in pre-treatment lung cancer patients (N = 26) while preserving specificity in healthy controls (N = 13), and reveal relationships between homologous recombination repair (HRR) gene function and homologous recombination deficiency (HRD) mediated by promoter methylation-driven biallelic loss of HRR genes in gynecologic cancer patients (N = 27). For practical convenience, this method was also implemented on qPCR platform with high performance (0.5% limit of detection). With its adaptability and potential utility in ctDNA detection and treatment, this approach holds promise for advancing clinical diagnostics.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"1825-1841"},"PeriodicalIF":9.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224758","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":"Loss of p300 in proximal tubular cells reduces renal fibrosis and endothelial-mesenchymal transition.","authors":"Hyunsik Kim,Soo-Yeon Park,Soo Yeon Lee,Jae-Hwan Kwon,Seunghee Byun,Byounghwi Ko,Jung-Yoon Yoo,Beom Seok Kim,Beom Jin Lim,Ho-Geun Yoon","doi":"10.1038/s44321-025-00243-1","DOIUrl":"https://doi.org/10.1038/s44321-025-00243-1","url":null,"abstract":"Chronic kidney disease (CKD) has a high prevalence worldwide and is typically accompanied by severe fibrosis. However, the exact pathogenesis of renal fibrosis and effective treatments have yet to be identified. In this study, we found that expression of the histone-acetyltransferase p300 was increased in focal segmental glomerulosclerosis patients and several distinct mouse models of renal fibrosis. Moreover, we showed that the AKT-mediated phosphorylation of Ser-1834 of p300 increased the stability of p300 upon renal fibrosis induction, and conversely, PPM1K specifically dephosphorylated p300 at Ser-1834, resulting in a significant reduction in p300 stability and renal fibrosis. Interestingly, increased p300 in proximal tubular cells (PTCs) promoted renal fibrosis development by mediating the endothelial to mesenchymal transition (EndMT) via upregulation of the mesenchymal-transition-related secreted proteins POSTN, FSTL1, and FSCN1. Both EndMT and renal fibrosis were significantly diminished by either PTC-specific deletion of p300 gene or selective inhibitors of p300. Collectively, our results demonstrate the role of p300 in the development of renal fibrosis, and suggest that p300 is a promising target for treatment of advanced CKD.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"19 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521217","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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