EMBO Molecular MedicinePub Date : 2026-10-01Epub Date: 2026-08-22DOI: 10.1038/s44321-026-00490-w
Dimitrios Doultsinos, Ingrid Tomljanovic, Eleftherios Pilalis, Sophia M Abusamra, Mohammed Alshalalfa, Romuald Parmentier, Vidhula Ahire, Imogen E Bridges, Sandy Figiel, Joanna Hester, Damien Leach, Ashwin Nandakumar, Rensheng Wan, Yanis Zekri, Jichang Zhang, Charlotte L Bevan, Edward O'Neill, Alastair D Lamb, Valentine Macauley, Jean Phillipe Theurillat, Alfonso Urbanucci, R Jeffrey Karnes, Daniel E Spratt, Elai Davicioni, David Quigley, Wilbert Zwart, Clementine Le Magnen, Aristotelis Chatziioannou, Ian G Mills
{"title":"IRE1 activity is prognostic in localised and metastatic prostate cancer and affects epithelial lineage states.","authors":"Dimitrios Doultsinos, Ingrid Tomljanovic, Eleftherios Pilalis, Sophia M Abusamra, Mohammed Alshalalfa, Romuald Parmentier, Vidhula Ahire, Imogen E Bridges, Sandy Figiel, Joanna Hester, Damien Leach, Ashwin Nandakumar, Rensheng Wan, Yanis Zekri, Jichang Zhang, Charlotte L Bevan, Edward O'Neill, Alastair D Lamb, Valentine Macauley, Jean Phillipe Theurillat, Alfonso Urbanucci, R Jeffrey Karnes, Daniel E Spratt, Elai Davicioni, David Quigley, Wilbert Zwart, Clementine Le Magnen, Aristotelis Chatziioannou, Ian G Mills","doi":"10.1038/s44321-026-00490-w","DOIUrl":"10.1038/s44321-026-00490-w","url":null,"abstract":"<p><p>Prostate cancer (PCa) is an androgen receptor (AR) driven, high-incidence disease significantly contributing to cancer mortality. To improve treatment outcomes for patients at high risk of metastasis, PCa is in need of better risk stratification at diagnosis. The unfolded protein response (UPR) is an AR-dependent process. However, the impact of the UPR transducer IRE1 on AR-dependent biology and acquired treatment resistance has not been defined. We use pre-clinical models of stress response to describe the impact of IRE1 activity loss on multiple PCa stages and demonstrate its involvement with poor prognosis (RB1 loss), and cell lineage determination (club-like phenotypes). Integrating clinical transcriptomic datasets, we chart IRE1 activity throughout PCa evolution and develop an IRE1 activity signature (IRE1sig1.0) reflecting both tumoral and micro-environmental stress responses. IRE1sig1.0 correlates with tumoral identity, and prognosticates localised and metastatic disease independently from AR activity. Using IRE1sig1.0 as a tool may inform ARSI suitability and guide IRE1 modulation as a novel combination therapeutic in prostate cancer.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"3898-3938"},"PeriodicalIF":7.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148789706","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 : 2026-10-01Epub Date: 2026-10-12DOI: 10.1038/s44321-026-00514-5
Young Jae Moon, Nikki McCormack, Thomas Diehn, Stephen Lin, Katia Staedler, Surajit Bhattacharya, Daniel C Bittel, Paul C Wang, Marshall Hogarth, Jong-Sung Oh, Tae Sik Goh, Ji Hong Min, Tanya Stojkovic, Isabelle Ackermann-Bonan, Jyoti K Jaiswal
{"title":"FAP adipogenesis drives early spinal muscle loss in dysferlinopathy and reveals a therapeutic target.","authors":"Young Jae Moon, Nikki McCormack, Thomas Diehn, Stephen Lin, Katia Staedler, Surajit Bhattacharya, Daniel C Bittel, Paul C Wang, Marshall Hogarth, Jong-Sung Oh, Tae Sik Goh, Ji Hong Min, Tanya Stojkovic, Isabelle Ackermann-Bonan, Jyoti K Jaiswal","doi":"10.1038/s44321-026-00514-5","DOIUrl":"10.1038/s44321-026-00514-5","url":null,"abstract":"<p><p>Dysferlinopathy (Limb Girdle Muscular Dystrophy R2/LGMD2B) causes progressive weakness of limb-girdle muscles. Although gait abnormalities are common, the contribution of spinal muscles to disease symptoms remains poorly understood. Using cross-sectional MRI in patients and longitudinal analyses in a dysferlinopathic mouse model, we identify early-onset, progressive adipogenic degeneration of spinal muscles as a previously unrecognized hallmark of dysferlinopathy. Multiple spinal muscles, including the iliocostalis, longissimus, and spinalis, are affected, with degeneration preceding pathology in limb muscles. In mice, early spinal muscle loss is associated with altered posture and gait, implicating axial muscle degeneration as a functional driver of disease. Mechanistically, spinal muscle degeneration is accompanied by an intrinsic increase in adipogenic differentiation of spinal fibroadipogenic progenitors (FAPs). Transcriptomic profiling implicated HDAC and Wnt/ß-catenin signaling as the main regulators of FAP adipogenic shift. Pharmacological inhibition of either pathway suppressed adipogenic differentiation of dysferlinopathic FAPs in vitro, with in vivo inhibition of GSK3 reducing adipogenic degeneration in spinal and injured limb muscles. These findings establish early spinal muscle degeneration as a key pathological feature of dysferlinopathy and identify GSK3 signaling as a promising therapeutic target.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"18 10","pages":"4034-4058"},"PeriodicalIF":7.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165285","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":"A cavity-reduced prefusion RSV F bivalent vaccine elicits durable and protective immunity.","authors":"Lijie Liu, Mengrong Yan, Ruoxu Liang, Qingxin Wu, Changbin Qu, Huiqi Wu, Zhi Liao, Huiyu Chen, Jingjing Zou, Zeyun Sun, Dongyu Niu, Liyuan Wu, Li Zhao, Jialing Dai, Jialun Shen, Long Zhang, Wei Zhang, Wei Peng","doi":"10.1038/s44321-026-00511-8","DOIUrl":"10.1038/s44321-026-00511-8","url":null,"abstract":"<p><p>Respiratory syncytial virus (RSV) remains a major cause of severe respiratory disease, and stabilization of the prefusion (preF) conformation of the F glycoprotein is central for vaccine development. Here, we report a structure-guided engineering strategy that enhances preF stability by reducing the hydrophobic cavity within the trimeric F protein. Targeted modifications at metastability-associated sites generated RVF-88, a disulfide-free stabilized preF immunogen that preserves key neutralizing epitopes, including antigenic site Ø, while exhibiting improved structural integrity and long-term storage stability. Formulated as an unadjuvanted bivalent vaccine, RVF-88 elicited potent neutralizing antibody responses and durable immune protection lasting up to 5 months in mice. Vaccination also protected both mice and cotton rats against RSV challenge. Structural analyses confirmed the intended cavity-reduction design, revealing a reduced apical hydrophobic cavity volume and surface area while maintaining the prefusion architecture. Together, these findings establish hydrophobic cavity reduction as a rational strategy for stabilizing prefusion RSV F and provide a promising next-generation vaccine candidate with improved stability and immunogenicity for further clinical development.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"3979-4000"},"PeriodicalIF":7.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148857025","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":"Methyltransferase-assisted single duplex sequencing for detecting circulating tumor DNA.","authors":"Zhaoyu Jiang, Yuxuan Wu, Yuqing Guo, Renjie Luo, Wei Wang, Fuchou Tang, Wei Fu, Xin Zhou, Lu Wen","doi":"10.1038/s44321-026-00509-2","DOIUrl":"10.1038/s44321-026-00509-2","url":null,"abstract":"<p><p>Accurate circulating tumor DNA (ctDNA) detection is limited by high sequencing errors. To address this, we developed Methyltransferase-Assisted Single Duplex sequencing (MASD-seq), which physically links Watson and Crick strands to enable error correction using double-stranded information within a single read pair. MASD-seq employs enzymatic methyl-sequencing to disrupt strand pairing and uses CpG methyltransferase pre-methylation to enable detection of CpG>TpG and transversion mutations in DNA duplexes. In parallel, MspI digestion enriches tumor CpG>TpG mutations and reduces genome complexity. MASD-seq achieves error rates of 5.4 × 10<sup>-7</sup> for CpG>TpG and 4.1 × 10<sup>-8</sup> for transversions in cell lines, allowing detection of age-associated mutational burdens in blood. Tissue analyses show a 4-fold enrichment of CpG>TpG mutations and a 1.6-fold increase in total mutations in high microsatellite instability (MSI-H) colorectal cancer (CRC), and 3-fold and 1.2-fold enrichments in microsatellite stable (MSS) tumors, respectively, yielding a correctable mutation burden comparable to the whole genome. Clinical testing demonstrates an area under the curve (AUC) of 0.97 for ctDNA detection in CRC patients. MASD-seq is a highly accurate sequencing method, suggesting its potential for future clinical applications.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"3961-3978"},"PeriodicalIF":7.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148789644","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 : 2026-10-01Epub Date: 2026-09-12DOI: 10.1038/s44321-026-00520-7
Mirko Luoni, Stefano Parracino, Serena G Giannelli, Francesca Morosi, Elisa Ventura, Agostina Di Pizio, Sharon Muggeo, Angelo Iannielli, Silvia Sicardi, Tamara Canu, Tommaso Russo, Antonio Esposito, Ubaldo Del Carro, Fabio Pastorino, Vania Broccoli
{"title":"Targeted AAV gene therapy for neuroblastoma via direct capsid-antibody coupling.","authors":"Mirko Luoni, Stefano Parracino, Serena G Giannelli, Francesca Morosi, Elisa Ventura, Agostina Di Pizio, Sharon Muggeo, Angelo Iannielli, Silvia Sicardi, Tamara Canu, Tommaso Russo, Antonio Esposito, Ubaldo Del Carro, Fabio Pastorino, Vania Broccoli","doi":"10.1038/s44321-026-00520-7","DOIUrl":"10.1038/s44321-026-00520-7","url":null,"abstract":"<p><p>Adeno-associated viral (AAV) vectors are widely used in gene therapy for their versatility and safety, but their broad tropism limits cell-specific applications such as targeting primary or metastatic tumor cells. To address this, we developed AAV-STITCH, a strategy using SpyTag technology to covalently attach polypeptides to the AAV capsid. This allows precise, dose-dependent coupling of an anti-GD2 scFv to a galactose-binding-deficient AAV9-W503A capsid, redirecting tropism specifically to GD2-expressing neuroblastoma (NB) cells. In pseudometastatic xenograft mouse models, AAV-STITCHαGD2 selectively transduced NB tumor cells without transduction of healthy liver tissue. Furthermore, delivery of a suicide gene via AAV-STITCHαGD2 significantly slowed tumor growth and extended survival in mice with subcutaneous and pseudometastatic NB xenografts. When combined with standard-of-care chemotherapy for relapsed NB, AAV-STITCHαGD2 produced robust curative effects. Collectively, these results demonstrate the feasibility of engineering AAVs with highly specific transduction properties, providing a versatile platform for targeted tumor cell suppression and advancing the development of next-generation, precision gene therapies for cancer.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"4117-4152"},"PeriodicalIF":7.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955098","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":"Extracellular RNA clearance by non-canonical cell-surface MDA5 protects against lung fibrosis.","authors":"Takashi Ishii, Masafumi Horie, Hirokazu Urushiyama, Yusuke Murakami, Tomoya Narita, Ryutaro Fukui, Kensuke Miyake, Akira Saito, Naomi Yamashita, Keiki Kumano, Hidenori Kage","doi":"10.1038/s44321-026-00513-6","DOIUrl":"10.1038/s44321-026-00513-6","url":null,"abstract":"<p><p>The role of innate immune receptors, specifically RNA sensors, in non-pathogen-driven lung fibrosis remains unclear. Here, we demonstrate that the cytosolic RNA sensor MDA5 could translocate to the cell surface upon bleomycin-induced damage. MDA5-deficient mice exhibited exacerbated lung fibrosis with increased IL-17A⁺ γδ T cells and neutrophils, which is independent of the canonical MAVS pathway and type I interferon signaling. Phenotypically, MDA5-deficient lung CD11b⁺ macrophages, which resemble human SPP1⁺ macrophages, showed elevated expression of CCR2 ligands. Mechanistically, cell-surface MDA5 acts as a scavenger receptor that captures extracellular self-RNA and shuttles it for lysosomal degradation. Loss of MDA5 leads to aberrant cellular RNA accumulation, triggering TLR8-dependent hyperproduction of CCR2 ligands. Analysis of human lung fibrosis samples from public datasets revealed SPP1⁺ macrophages are a major source of CCR2 ligands, suggesting their potential to activate monocytes. Our findings reveal an unrecognized protective function of MDA5 in lung fibrosis: preventing TLR8-mediated hyperinflammation through the lysosomal clearance of extracellular RNA. This mechanism provides crucial insights into the pathogenesis of fibrotic diseases like interstitial lung diseases.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"18 10","pages":"4001-4033"},"PeriodicalIF":7.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165249","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 : 2026-10-01Epub Date: 2026-08-27DOI: 10.1038/s44321-026-00507-4
Tingxi Guo, Kaya R Epstein, Maegan E Hoover, Nathan W Zammit, Jennifer Y Yam, Scott Hussell, Sophia Hernandez, Abigail Doherty, Payam Zarin, Martina Sassone-Corsi, Lindsay Webb, Gene I Uenishi, Thomas Wickham, Christopher L Moore
{"title":"A synthetic NKG2A engager enables long-term persistence of HLA-deficient allogeneic engineered Tregs.","authors":"Tingxi Guo, Kaya R Epstein, Maegan E Hoover, Nathan W Zammit, Jennifer Y Yam, Scott Hussell, Sophia Hernandez, Abigail Doherty, Payam Zarin, Martina Sassone-Corsi, Lindsay Webb, Gene I Uenishi, Thomas Wickham, Christopher L Moore","doi":"10.1038/s44321-026-00507-4","DOIUrl":"10.1038/s44321-026-00507-4","url":null,"abstract":"<p><p>Allogeneic cell therapies offer a scalable and off-the-shelf alternative to the autologous approach, but immune rejection, particularly by natural killer (NK) cells following human leukocyte antigen (HLA) ablation, remains a major barrier to their persistence. Here, we report an improved synthetic NKG2A engager to selectively inhibit NKG2A⁺ NK cells while avoiding activation of NKG2C⁺ subsets, thereby overcoming a key limitation of the natural ligand HLA-E. Engineered regulatory T cells (EngTregs) lacking HLA and expressing the engager were protected from in vitro NK cell-mediated cytotoxicity more effectively than previously reported NK inhibitory strategies. In humanized mouse models, EngTregs persisted for up to 12 weeks, whereas unprotected cells were rapidly rejected. Incorporation of the engager into a clinically compatible dual-AAV EngTregs preserved Treg identity and function while conferring resistance to immune rejection. Together, these findings establish the improved NKG2A engager as an effective synthetic immune-evasion strategy and provide a clinically translatable approach to enable durable persistence of off-the-shelf EngTreg therapies.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"3939-3960"},"PeriodicalIF":7.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839558","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 : 2026-10-01Epub Date: 2026-09-16DOI: 10.1038/s44321-026-00522-5
Jun Zhang
{"title":"Lysine pyruvylation: decoding the molecular language of pyruvate signaling.","authors":"Jun Zhang","doi":"10.1038/s44321-026-00522-5","DOIUrl":"10.1038/s44321-026-00522-5","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"3879-3882"},"PeriodicalIF":7.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982270","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 : 2026-10-01Epub Date: 2026-09-17DOI: 10.1038/s44321-026-00516-3
Anna Pia Plazzo, Verena Filz, Michaela Prothiwa, Rebekka Lambrecht, M Eugenia Delgado, Jennifer R Fleming, Jerome Duschek, Elia Pilgram, Juliane Friedrich, Raphael Eisenring, Lea Kurtz, Kerstin Stemmer, Lotta K Stenman, Fabian Amaya Garcia, Miriam Unterlass, Olga Mayans, Thomas Böttcher, Thomas Brunner
{"title":"Microbiome-host communication via vaccenic acid modulates LRH-1/NR5A2 activity and ameliorates metabolic liver disease.","authors":"Anna Pia Plazzo, Verena Filz, Michaela Prothiwa, Rebekka Lambrecht, M Eugenia Delgado, Jennifer R Fleming, Jerome Duschek, Elia Pilgram, Juliane Friedrich, Raphael Eisenring, Lea Kurtz, Kerstin Stemmer, Lotta K Stenman, Fabian Amaya Garcia, Miriam Unterlass, Olga Mayans, Thomas Böttcher, Thomas Brunner","doi":"10.1038/s44321-026-00516-3","DOIUrl":"10.1038/s44321-026-00516-3","url":null,"abstract":"<p><p>Interactions between microbiota and the host can profoundly affect human health. In particular, microbiota-derived metabolites influence liver physiology and contribute to the development of metabolic diseases, yet the molecular mechanisms underlying microbiome-host communication remain incompletely understood. Here, we identify bacterial lipids as modulators of the nuclear receptor Liver Receptor Homolog-1 (LRH-1/NR5A2), a regulator of hepatic metabolism. Lipid extracts from multiple bacterial species, including the probiotic Bifidobacterium animalis subsp. lactis B420<sup>TM</sup>, activated LRH-1, leading to the identification of the long-chain fatty acid vaccenic acid (VA) as a previously unrecognized endogenous LRH-1 ligand. VA directly bound the LRH-1 ligand-binding domain and stimulated receptor-dependent transcriptional activity. In high-fat diet-induced obese and hyperglycemic mice, VA-mediated LRH-1 activation improved glucose homeostasis and attenuated metabolic liver disease. Transcriptomic analyses revealed suppression of hepatic de novo lipogenesis as a principle downstream response to LRH-1 activation. Together, these findings establish a microbiota-LRH-1 signaling axis that links bacterial lipid metabolism to host metabolic regulation, identify VA as a functional LRH-1 agonist, and provide a mechanistic rationale for targeting LRH-1 in metabolic liver disease.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"4059-4089"},"PeriodicalIF":7.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988340","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 : 2026-10-01Epub Date: 2026-09-03DOI: 10.1038/s44321-026-00517-2
Bojan Jevtić, Milica Lazarević, Goran Stegnjaić, Suzana Stanisavljević, Ivan Pilipović, Neda Nikolovski, Zorana Milosavljević, Miljana Momčilović, Ivan Koprivica, Natalija Jonić, Dragica Mićanović, Nataša Radulović, Maša Marković, Ksenija Mirković, Danijela Mišić, Uroš Gašić, Filip Nikolić, Nikola Veselinović, Henrike Körner, Lukas Grimm, Dmitri Lodygin, Alexander Flügel, Graeme Fraser, Tamara Saksida, Mirjana Dimitrijević, Ivana Stojanović, Đorđe Miljković
{"title":"FFAR2 activation induces IL-22-dependent intestinal immune responses to suppress CNS autoimmunity.","authors":"Bojan Jevtić, Milica Lazarević, Goran Stegnjaić, Suzana Stanisavljević, Ivan Pilipović, Neda Nikolovski, Zorana Milosavljević, Miljana Momčilović, Ivan Koprivica, Natalija Jonić, Dragica Mićanović, Nataša Radulović, Maša Marković, Ksenija Mirković, Danijela Mišić, Uroš Gašić, Filip Nikolić, Nikola Veselinović, Henrike Körner, Lukas Grimm, Dmitri Lodygin, Alexander Flügel, Graeme Fraser, Tamara Saksida, Mirjana Dimitrijević, Ivana Stojanović, Đorđe Miljković","doi":"10.1038/s44321-026-00517-2","DOIUrl":"10.1038/s44321-026-00517-2","url":null,"abstract":"<p><p>Short-chain fatty acids (SCFA) protect against central nervous system (CNS) autoimmunity, but the receptor-mediated mechanisms underlying these effects remain poorly understood, limiting their therapeutic exploitation. Here, we show that selective oral activation of free fatty acid receptor 2 (FFAR2) with the synthetic agonist Cpd1 effectively ameliorates established experimental autoimmune encephalomyelitis (EAE), demonstrating therapeutic efficacy after the onset of the autoimmune response. Cpd1 treatment promoted regulatory T cells and type 3 innate lymphoid cells in the intestine while reducing inflammatory infiltration in the CNS, indicating that modulation of intestinal immunity is sufficient to restrain neuroinflammation. Transcriptomic analysis of intestinal CD4⁺ T cells revealed broad suppression of pathways controlling T-cell activation and proliferation. Mechanistically, the therapeutic effects of Cpd1 required interleukin-22 (IL-22), as antibody-mediated IL-22 neutralization abolished disease protection, identifying IL-22 as a key downstream effector of FFAR2 signaling. Together, these findings establish selective FFAR2 agonism as a tractable strategy to therapeutically modulate the gut-CNS immune axis and identify FFAR2 as a promising target for the treatment of multiple sclerosis and other autoimmune diseases.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"4090-4116"},"PeriodicalIF":7.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886698","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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