Rory K M Long, François Korbmacher, Paolo Ronchi, Hannah Fleckenstein, Martin Schorb, Waleed Mirza, Mireia Mallorquí, Ruth Aguilar, Gemma Moncunill, Yannick Schwab, Maria Bernabeu
{"title":"Plasmodium falciparum impairs Ang-1 secretion by pericytes in a 3D brain microvessel model.","authors":"Rory K M Long, François Korbmacher, Paolo Ronchi, Hannah Fleckenstein, Martin Schorb, Waleed Mirza, Mireia Mallorquí, Ruth Aguilar, Gemma Moncunill, Yannick Schwab, Maria Bernabeu","doi":"10.1038/s44321-025-00319-y","DOIUrl":"https://doi.org/10.1038/s44321-025-00319-y","url":null,"abstract":"<p><p>Disruption of the vascular protective angiopoietin-Tie axis is common in cerebral malaria (CM) patients, who display elevated angiopoietin-2 (Ang-2) and reduced angiopoietin-1 (Ang-1) blood concentrations. The role of pericytes in CM pathogenesis remains unexplored, despite being a major source of brain Ang-1 secretion and evidence of pericyte damage observed in CM postmortem samples. Here, we engineered a human 3D microfluidics-based brain microvessel model containing the minimal cellular components to replicate the angiopoietin-Tie axis, human primary brain microvascular endothelial cells, and pericytes. This model replicated pericyte vessel coverage and ultrastructural interactions present in the brain microvasculature. When exposed to P. falciparum-iRBC egress products, 3D brain microvessels presented decreased Ang-1 secretion, increased vascular permeability, and minor ultrastructural changes in pericyte morphology. Notably, P. falciparum-mediated barrier disruption was partially reversed after pre-treatment with recombinant Ang-1 and the Tie-2 activator, AKB-9778. Our approach suggests a novel mechanistic role of pericytes in CM pathogenesis and highlights the potential of therapeutics that target the angiopoietin-Tie axis to rapidly counteract vascular dysfunction caused by P. falciparum.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145307141","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}
Ang Li,Sen Huang,Shu-Qin Cao,Jinyi Lin,Linping Zhao,Feng Yu,Miaodan Huang,Lele Yang,Jiaqi Xin,Jing Wen,Lingli Yan,Ke Zhang,Maoyuan Jiang,Weidong Le,Peng Li,Yong U Liu,Dajiang Qin,Jiahong Lu,Guang Lu,Hanming Shen,Xiaoli Yao,Evandro F Fang,Huanxing Su
{"title":"Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy.","authors":"Ang Li,Sen Huang,Shu-Qin Cao,Jinyi Lin,Linping Zhao,Feng Yu,Miaodan Huang,Lele Yang,Jiaqi Xin,Jing Wen,Lingli Yan,Ke Zhang,Maoyuan Jiang,Weidong Le,Peng Li,Yong U Liu,Dajiang Qin,Jiahong Lu,Guang Lu,Hanming Shen,Xiaoli Yao,Evandro F Fang,Huanxing Su","doi":"10.1038/s44321-025-00323-2","DOIUrl":"https://doi.org/10.1038/s44321-025-00323-2","url":null,"abstract":"Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (n = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba, as a robust and specific mitophagy inducer. ISO enhances PINK1-Parkin-dependent mitophagy via stabilization of the PINK1/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in C. elegans and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1-Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"64 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296052","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}
Bauke V Schomakers, Adriana S Passadouro, Maria M Trętowicz, Pelle J Simpson, Yorrick R J Jaspers, Michel van Weeghel, Iman Man Hu, Cathelijne M E Lamboo, Denise Cloutier, Barry J Byrne, Jan Bert van Klinken, Paul M L Janssen, Sander R Piersma, Connie R Jimenez, Frédéric M Vaz, Gajja S Salomons, Jolanda van der Velden, Riekelt H Houtkooper, Signe Mosegaard
{"title":"Integrated multi-omics mapping of mitochondrial dysfunction and substrate preference in Barth syndrome cardiac tissue.","authors":"Bauke V Schomakers, Adriana S Passadouro, Maria M Trętowicz, Pelle J Simpson, Yorrick R J Jaspers, Michel van Weeghel, Iman Man Hu, Cathelijne M E Lamboo, Denise Cloutier, Barry J Byrne, Jan Bert van Klinken, Paul M L Janssen, Sander R Piersma, Connie R Jimenez, Frédéric M Vaz, Gajja S Salomons, Jolanda van der Velden, Riekelt H Houtkooper, Signe Mosegaard","doi":"10.1038/s44321-025-00320-5","DOIUrl":"https://doi.org/10.1038/s44321-025-00320-5","url":null,"abstract":"<p><p>Barth syndrome (BTHS) is a rare X-linked recessively inherited disorder caused by variants in the TAFAZZIN gene, leading to impaired conversion of monolysocardiolipin (MLCL) into mature cardiolipin (CL). Accumulation of MLCL and CL deficiency are diagnostic markers for BTHS. Clinically, BTHS includes cardiomyopathy, skeletal myopathy, neutropenia, and growth delays. Severely affected patients may require early cardiac transplants due to unpredictable cardiac phenotypes. The pathophysiological mechanisms of BTHS are poorly understood, and treatments remain symptomatic. This study analyzed heart samples from five pediatric male BTHS patients (5 months-15 years) and compared them to tissues from 24 non-failing donors (19-71 years) using an integrated omics method combining metabolomics, lipidomics, and proteomics. The analysis confirmed changes in diagnostic markers (CL and MLCL), severe mitochondrial alterations, metabolic shifts, and elevated heart-failure markers. It also revealed significant interindividual differences among BTHS patients. This study describes a powerful analytical tool for the in-depth analysis of metabolic disorders and a solid foundation for the understanding of BTHS disease phenotypes in cardiac tissues.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285785","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}
Yi Xiong,Fang Zeng,Kaiping Luo,Li Wang,Manna Li,Yanxia Chen,Tianlun Huang,Chengyun Xu,Gaosi Xu,Honghong Zou
{"title":"Glycine decarboxylase advances IgA nephropathy by boosting mesangial cell proliferation through the pyrimidine pathway.","authors":"Yi Xiong,Fang Zeng,Kaiping Luo,Li Wang,Manna Li,Yanxia Chen,Tianlun Huang,Chengyun Xu,Gaosi Xu,Honghong Zou","doi":"10.1038/s44321-025-00315-2","DOIUrl":"https://doi.org/10.1038/s44321-025-00315-2","url":null,"abstract":"The proliferation of glomerular mesangial cells is a fundamental pathological change in immunoglobulin A nephropathy (IgAN). This study aims to elucidate the mechanisms that affect the proliferation of glomerular mesangial cells. Bioinformatics analysis combined with clinical detection identified the key molecule glycine decarboxylase (GLDC). In vitro experiments revealed that GLDC knockdown reduces the proliferative effect of pIgA on mesangial cells. Pyrimidine metabolism is involved in the proliferation regulation of mesangial cells by GLDC. Additionally, GLDC's regulation of glycolysis in mesangial cells was discovered, which further affects the progression of renal fibrosis and the proliferation of glomerular mesangial cells. Upon knockdown of the key rate-limiting enzymes of pyrimidine metabolism, CAD and DHODH, the overexpression of GLDC lost its regulatory effect on glycolysis. The regulatory mechanisms described above were confirmed by inhibiting GLDC expression in the kidneys in vivo. In conclusion, GLDC upregulates pyrimidine metabolic flux, which subsequently fuels glycolysis to promote mesangial cell proliferation, promoting IgAN progression.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"1 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283453","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}
Marcel S Woo,Joseph Therriault,Seyyed Ali Hosseini,Yi-Ting Wang,Arthur C Macedo,Nesrine Rahmouni,Étienne Aumont,Stijn Servaes,Cécile Tissot,Jaime Fernandez-Arias,Lydia Trudel,Brandon Hall,Gleb Bezgin,Kely Quispialaya-Socualaya,Marina Goncalves,Tevy Chan,Jenna Stevenson,Yansheng Zheng,Stuart Mitchell,Robert Hopewell,Ilaria Pola,Kubra Tan,Guglielmo Di Molfetta,Firoza Z Lussier,Gassan Massarweh,Paolo Vitali,Jean-Paul Soucy,Serge Gauthier,Nicholas J Ashton,Kaj Blennow,Tharick A Pascoal,Henrik Zetterberg,Andréa L Benedet,Pedro Rosa-Neto
{"title":"Glia inflammation and cell death pathways drive disease progression in preclinical and early AD.","authors":"Marcel S Woo,Joseph Therriault,Seyyed Ali Hosseini,Yi-Ting Wang,Arthur C Macedo,Nesrine Rahmouni,Étienne Aumont,Stijn Servaes,Cécile Tissot,Jaime Fernandez-Arias,Lydia Trudel,Brandon Hall,Gleb Bezgin,Kely Quispialaya-Socualaya,Marina Goncalves,Tevy Chan,Jenna Stevenson,Yansheng Zheng,Stuart Mitchell,Robert Hopewell,Ilaria Pola,Kubra Tan,Guglielmo Di Molfetta,Firoza Z Lussier,Gassan Massarweh,Paolo Vitali,Jean-Paul Soucy,Serge Gauthier,Nicholas J Ashton,Kaj Blennow,Tharick A Pascoal,Henrik Zetterberg,Andréa L Benedet,Pedro Rosa-Neto","doi":"10.1038/s44321-025-00316-1","DOIUrl":"https://doi.org/10.1038/s44321-025-00316-1","url":null,"abstract":"Accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are followed by the activation of glia cells and infiltration of peripheral immune cells that collectively accelerate neurodegeneration in preclinical AD models. Yet, the role of neuroinflammation for neuronal injury and disease progression in preclinical and early symptomatic AD remains elusive. Here, we combined multiplexed immunoassays and SomaScan proteomics of the cerebrospinal fluid (CSF) with MRI and PET brain imaging of people across the AD continuum to identify pathways that are associated with AD progression. Unbiased clustering revealed that glia-mediated inflammation, activation of cell death pathways (CDPs) and synaptic pathologies were among the earliest Aβ-induced changes, and were associated with disease progression in preclinical AD. Mediation analysis revealed that activation of CDPs were decisive drivers of inflammation in early symptomatic AD. The cycle of glia-mediated neuroinflammation and neuronal injury characterizes preclinical AD and has implications for novel treatment approaches.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"7 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261446","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":"Brown remodeling of white adipose tissue protects against abdominal aortic aneurysm via batokine FSTL1.","authors":"Chunling Huang,Yuna Huang,Boshui Huang,Lei Yao,Zenghui Zhang,Luoxiao Dong,Chang Guan,Junping Li,Zhaoqi Huang,Sixu Chen,Yuan Jiang,Yuling Zhang,Jingfeng Wang,Yangxin Chen,Zhaoyu Liu","doi":"10.1038/s44321-025-00318-z","DOIUrl":"https://doi.org/10.1038/s44321-025-00318-z","url":null,"abstract":"Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without effective medical therapies. Emerging evidence have suggested a crosstalk between adipose tissue and vascular cells. Besides, brown adipose tissue is considered beneficial for cardiovascular health. Nevertheless, whether brown remodeling of white adipose tissue would protect against AAA remains unclear. Here, we showed that patients with AAA had a decreased browning level of adipose tissue, and induction of adipose tissue browning significantly reduced AAA incidence and attenuated AAA development in mice. Using LC-MS/MS and proteomic analysis, we further identified Follistatin-like 1 (FSTL1) as a novel vessel-protective adipokine secreted by browning adipocytes. Mechanistically, FSTL1 inhibited VSMC apoptosis through DIP2A/AKT signaling. Furthermore, we demonstrated that adipocyte-specific deficiency of FSTL1 abrogated the protective effect of browning induction. Moreover, supplementation of FSTL1 either systemically or patched into hydrogel placing around the abdominal aorta markedly limited aortic dilation and AAA progression. Our data suggest a protective role of adipose tissue browning and batokine FSTL1 in the development of AAA, which may represent a novel intervention strategy for AAA.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"29 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254535","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}
Yibo Hou,Zixian Wang,Wenlin Wang,Qing Tang,Yongde Cai,Siyang Yu,Jin Wang,Xiu Yan,Guocai Wang,Peter E Lobie,Yubo Zhang,Xiaoyong Dai,Shaohua Ma
{"title":"AI-identified CD133-targeting natural compounds demonstrate differential anti-tumor effects and mechanisms in pan-cancer models.","authors":"Yibo Hou,Zixian Wang,Wenlin Wang,Qing Tang,Yongde Cai,Siyang Yu,Jin Wang,Xiu Yan,Guocai Wang,Peter E Lobie,Yubo Zhang,Xiaoyong Dai,Shaohua Ma","doi":"10.1038/s44321-025-00308-1","DOIUrl":"https://doi.org/10.1038/s44321-025-00308-1","url":null,"abstract":"Advanced algorithms have significantly improved the efficiency of in vitro screening for protein-interactive compounds. However, target antigen (TAA/TSA)-based drug discovery remains challenging, as predictions of compound-protein interaction (CPI) based solely on molecular structure fail to fully elucidate the underlying mechanisms. In this study, we utilized deep learning, specifically TransformerCPI to screen active molecules from a Chinese herb compound library based on protein sequences. Two natural products, Polyphyllin V and Polyphyllin H, were identified as targeting the pan-cancer marker CD133. Their anti-tumor efficacy and safety were confirmed across validation in cancer cell lines, tumor patient-derived organoids, and animal models. Despite their analogous structures and binding affinity to CD133, Polyphyllin V suppresses the PI3K-AKT pathway, inducing pyroptosis and blockage of mitophagy, whereas Polyphyllin H inhibits the Wnt/β-catenin pathway and triggers apoptosis. These distinct mechanisms underscore the potential of combining AI-driven screening with biological validation. This AI-to-patient pipeline identifies Polyphyllin V and Polyphyllin H as CD133-targeted drugs for pan-cancer therapy, and reveals the limitations of virtual screening alone and emphasizes the necessity of live model evaluation in AI-based therapeutic discovery.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"98 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209250","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}
Aman P Mann, Sazid Hussain, Pablo Scodeller, Hope N B Moore, Elan Sherazee, Rachel M Russo, Erkki Ruoslahti
{"title":"A neuroprotective tetrapeptide for treatment of acute traumatic brain injury.","authors":"Aman P Mann, Sazid Hussain, Pablo Scodeller, Hope N B Moore, Elan Sherazee, Rachel M Russo, Erkki Ruoslahti","doi":"10.1038/s44321-025-00312-5","DOIUrl":"https://doi.org/10.1038/s44321-025-00312-5","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is a major clinical problem because of the high incidence and the severity of the subsequent sequelae. Despite extensive efforts, there are no therapeutic drugs clinically approved for treating acute TBI patients. To address this unmet need, we assessed the activity of the tetrapeptide, CAQK, in mice. When administered intravenously shortly after moderate or severe TBI, CAQK accumulates in the injured brain in mice and pigs. CAQK binds to an extracellular matrix glycoprotein complex that is upregulated in injured brain. Treatment of TBI mice with CAQK resulted in reduction in the size of the injury compared to control mice. There was reduced upregulation of the glycoprotein complex, less apoptosis, and lower expression of inflammatory markers in the injured area, indicating that CAQK alleviates neuroinflammation and the ensuing secondary injury. CAQK treatment also improved functional deficit in TBI mice, with no overt toxicity. Our findings suggest that CAQK may have therapeutic applications in TBI.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205828","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 : 2025-10-01Epub Date: 2025-08-22DOI: 10.1038/s44321-025-00295-3
Lucie Bracq, Audrey Chuat, Béatrice Kunz, Olivier Burri, Romain Guiet, Julien Duc, Nathalie Brandenberg, F Gisou van der Goot
{"title":"Injury-induced intestinal stem cell renewal requires capillary morphogenesis gene 2.","authors":"Lucie Bracq, Audrey Chuat, Béatrice Kunz, Olivier Burri, Romain Guiet, Julien Duc, Nathalie Brandenberg, F Gisou van der Goot","doi":"10.1038/s44321-025-00295-3","DOIUrl":"10.1038/s44321-025-00295-3","url":null,"abstract":"<p><p>Patients with the rare genetic disorder Hyaline Fibromatosis Syndrome (HFS) often succumb before 18 months of age due to severe diarrhea. As HFS is caused by loss-of-function mutations in the gene encoding capillary morphogenesis gene 2 (CMG2), these symptoms highlight a critical yet unexplored role for CMG2 in the gut. Here, we demonstrate that CMG2 knockout mice exhibit normal colon morphology and no signs of inflammation until the chemical induction of colitis. In these conditions, the colons of knockout mice do not regenerate despite previously experiencing similarly severe colitis, due to an inability to replenish their intestinal stem cell pool. Specifically, CMG2 knockout impairs the transition from fetal-like to Lgr5+ adult stem cells, which is associated with a defect in ß-catenin nuclear translocation. Based on our findings, we propose that CMG2 functions as a context-specific modulator of Wnt signaling, essential for replenishing the pool of intestinal stem cells following injury. This study provides new insights into the molecular mechanisms underlying lethal diarrhea in HFS and offers a broader understanding of fetal-like regenerative responses.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2612-2631"},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12514029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947174","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 : 2025-10-01Epub Date: 2025-08-29DOI: 10.1038/s44321-025-00296-2
Lise Brault, Edwige Voisset, Mathieu Desaunay, Antonia Boudet, Paraskevi Kousteridou, Sébastien Letard, Nadine Carbuccia, Armelle Goubard, Rémy Castellano, Yves Collette, Julien Vernerey, Isabelle Vigon, Jean-Max Pasquet, Patrice Dubreuil, Sophie Lopez, Paulo De Sepulveda
{"title":"Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML.","authors":"Lise Brault, Edwige Voisset, Mathieu Desaunay, Antonia Boudet, Paraskevi Kousteridou, Sébastien Letard, Nadine Carbuccia, Armelle Goubard, Rémy Castellano, Yves Collette, Julien Vernerey, Isabelle Vigon, Jean-Max Pasquet, Patrice Dubreuil, Sophie Lopez, Paulo De Sepulveda","doi":"10.1038/s44321-025-00296-2","DOIUrl":"10.1038/s44321-025-00296-2","url":null,"abstract":"<p><p>The heterogeneity of leukemic cells is the main cause of resistance to therapy in acute myeloid leukemia (AML). Consequently, innovative therapeutic approaches are critical to target a wide spectrum of leukemic clones, regardless of their genetic and non-genetic complexity. In this report, we leverage the vulnerability of AML cells to CDK6 to identify a combination therapy capable of targeting common biological processes shared by all leukemic cells, while sparing non-transformed cells. We demonstrate that the combined inhibition of CDK6 and LSD1 restores myeloid differentiation and depletes the leukemic progenitor compartment in AML samples. Mechanistically, this combination induces major changes in chromatin accessibility, leading to the transcription of differentiation genes and diminished LSC signatures. Remarkably, the combination is synergistic, induces durable changes in the cells, and is effective in PDX mouse models. While many AML samples exhibit only modest responses to LSD1 inhibition, co-targeting CDK6 restores the expected transcription response associated with LSD1 inhibition. Given the availability of clinical-grade CDK6 and LSD1 inhibitors, this combination holds significant potential for implementation in clinical settings through drug repositioning.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2632-2660"},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12514269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947135","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}
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