Science Translational Medicine最新文献

{"title":"Erratum for the Research Article “Engineering a highly elastic human protein–based sealant for surgical applications” by N. Annabi et al.","authors":"","doi":"10.1126/scitranslmed.aea4285","DOIUrl":"10.1126/scitranslmed.aea4285","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740575","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":"Viral spike antigen clearance and augmented recovery in children with post-COVID multisystem inflammatory syndrome treated with larazotide","authors":"Lael M. Yonker,&nbsp;Abigail S. Kane,&nbsp;Zoe Swank,&nbsp;Lena Papadakis,&nbsp;Victoria Kenyon,&nbsp;Samuel Han,&nbsp;Rosiane Lima,&nbsp;Lauren B. Guthrie,&nbsp;Bryan Alvarez-Carcamo,&nbsp;Manuella Lahoud-Rahme,&nbsp;Duraisamy Balaguru,&nbsp;Ryan W. Carroll,&nbsp;Josephine Lok,&nbsp;Chadi El Saleeby,&nbsp;David R. Walt,&nbsp;Alessio Fasano","doi":"10.1126/scitranslmed.adu4284","DOIUrl":"10.1126/scitranslmed.adu4284","url":null,"abstract":"<div >Multisystem inflammatory syndrome (MIS) is a severe disease that occurs weeks to months after acute infection with SARS-CoV-2, often occurring in children (MISC). Symptoms include high fever, rash, nausea, diarrhea, and abdominal pain. Children with MISC can develop cardiovascular injury including ventricular failure, coronary artery aneurysms, or shock. Current treatment strategies for these postacute sequelae of COVID-19 primarily target the hyperinflammatory response. However, a potential role for viral spike protein translocated via zonulin-mediated trafficking from gastrointestinal reservoirs of SARS-CoV-2 into the circulation has been suggested. Here, we report results from a phase 2a randomized, double-blind, placebo-controlled clinical trial testing the zonulin antagonist larazotide in 12 children with MISC with a median age of 5.7 years. Children were enrolled during hospitalization for acute MISC and were treated with adjuvant larazotide therapy four times daily for 3 weeks. Patients were monitored for 24 weeks for safety follow-up. No larazotide-related adverse events were reported. The concentration of SARS-CoV-2 spike protein antigen in blood samples correlated with inflammatory markers, including interferon-γ (IFN-γ) (<i>P</i> = 0.004) and interleukin-6 (IL-6) (<i>P</i> &lt; 0.0001), and with gastrointestinal symptoms as assessed by the PedsQL GI symptom score (<i>P</i> = 0.003). Children treated with larazotide displayed faster resolution of gastrointestinal symptoms, faster clearance of spike antigen, and a faster return to usual activities. Our findings suggest that larazotide treatment may be safe in children and may improve resolution of symptoms when used as an adjuvant therapy for MISC.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737509","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":"Human inner ear fluid imbalance detected by optical coherence tomography correlates with hearing loss","authors":"Wihan Kim,&nbsp;Dorothy W. Pan,&nbsp;Bong Jik Kim,&nbsp;Zihan Yang,&nbsp;Marcela Moran Mojica,&nbsp;Joni K. Doherty,&nbsp;Seiji B. Shibata,&nbsp;Brian E. Applegate,&nbsp;John S. Oghalai","doi":"10.1126/scitranslmed.adv3783","DOIUrl":"10.1126/scitranslmed.adv3783","url":null,"abstract":"<div >Hearing loss and vertigo occur when there is an imbalance between the two inner ear fluids, endolymph and perilymph. The inner ear is a small delicate structure encased in dense bone deep in the base of the skull, making it challenging to image with high resolution. Because the fluid chambers are so small, there is no reliable way to measure their balance in a living patient to guide therapy. Here, we translated the technology of optical coherence tomography (OCT) for use in the human inner ear. Peering through the otic capsule bone during mastoid surgery, we imaged the lateral and posterior semicircular canals of patients with Ménière’s disease or vestibular schwannoma and measured the endolymph-to-perilymph ratio. Compared with normal controls, both patient groups demonstrated increased endolymph and reduced perilymph, a disorder termed endolymphatic hydrops. OCT imaging demonstrated good repeatability for measuring the endolymph-to-perilymph ratio. Our data indicate that increased endolymph-to-perilymph ratios correlated with the degree of hearing loss. Thus, small yet meaningful changes in inner ear fluid balance are detectable with this approach with better resolution than gadolinium-enhanced 3 Tesla magnetic resonance imaging, the current gold standard clinical imaging modality. Our findings support the feasibility of imaging the human inner ear during surgical procedures with OCT and demonstrate the ability to detect endolymphatic hydrops. Moreover, this technique permits the measurement of the fluid chambers within the inner ear in real time during surgical procedures with adequate sensitivity to guide the management of complex but common ear diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 808","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684765","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":"Preexisting immunity to the 2009 pandemic H1N1 virus reduces susceptibility to H5N1 infection and disease in ferrets","authors":"Katherine H. Restori,&nbsp;Veronika Weaver,&nbsp;Devanshi R. Patel,&nbsp;Grace A. Merrbach,&nbsp;Kayla M. Septer,&nbsp;Cassandra J. Field,&nbsp;Michael J. Bernabe,&nbsp;Ethan M. Kronthal,&nbsp;Allen Minns,&nbsp;Scott E. Lindner,&nbsp;Seema S. Lakdawala,&nbsp;Valerie Le Sage,&nbsp;Troy C. Sutton","doi":"10.1126/scitranslmed.adw4856","DOIUrl":"10.1126/scitranslmed.adw4856","url":null,"abstract":"<div >Zoonotic infections with emerging influenza viruses occur in the context of population-wide immunity to seasonal strains. Because of the worldwide spread of highly pathogenic clade 2.3.4.4b H5N1 influenza viruses in wild birds, there have been numerous spillover events into mammals. This includes a recent spillover into dairy cows that started an ongoing outbreak across the United States. Human infections with avian and bovine origin H5N1 influenza viruses have been documented, raising concern that these viruses may cause a pandemic. Therefore, using a ferret model, we evaluated the impact of preexisting, infection-elicited immunity on susceptibility to H5N1 infection and on severity of disease. Preexisting immunity to the 2009 pandemic H1N1 influenza virus prevented severe H5N1 disease and reduced susceptibility to infection through direct contact with an infected donor ferret. These studies demonstrate that preexisting immunity to influenza viruses, especially the 2009 pandemic H1N1 virus, is a barrier to infection and disease caused by clade 2.3.4.4b H5N1 viruses.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 808","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adw4856","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684766","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":"Tissue-resident memory CD4+ T cells infiltrate the CNS in progressive multiple sclerosis and contribute to chronic autoimmunity in mice","authors":"Aurora Pignata,&nbsp;David Frieser,&nbsp;Carmen Gonzalez-Fierro,&nbsp;Cheng-Chih Hsiao,&nbsp;Hendrik J. Engelenburg,&nbsp;Marine Alis,&nbsp;Ilan Fijalkow,&nbsp;Vincent Cazaentre,&nbsp;Lucie Nozeran,&nbsp;Romain Miranda-Capet,&nbsp;Eloïse Dufourd,&nbsp;Thaïs Vermeulen,&nbsp;Amel Aïda,&nbsp;Carole Le Coz,&nbsp;Klaas Van Gisbergen,&nbsp;Nicolas Blanchard,&nbsp;Jörg Hamann,&nbsp;Joost Smolders,&nbsp;Roland S. Liblau,&nbsp;Frederick Masson","doi":"10.1126/scitranslmed.adp8109","DOIUrl":"10.1126/scitranslmed.adp8109","url":null,"abstract":"<div >Preventing T cell migration to the central nervous system (CNS) has remarkable therapeutic effects in relapsing-remitting multiple sclerosis (RRMS) but is poorly effective against the progressive form (PMS). Disability progression in PMS likely results from an interplay between smoldering local inflammation and neurodegeneration. The mechanisms sustaining the chronicity of PMS are poorly understood. Here, we investigated the potential role of tissue-resident memory CD4⁺ T cells (CD4⁺ Trm cells) in sustaining chronic CNS autoimmunity. We showed that CD4⁺ Trm cells were present in the CNS of mice with chronic experimental autoimmune encephalomyelitis (EAE) and in brain tissues from persons with PMS. Using flow cytometry and immunohistofluorescence analysis, we revealed the presence of bona fide CD4⁺ Trm cells expressing characteristic Trm cell surface markers, including CD69, CXCR6, P2RX7, and CD49a, in the CNS of mice with EAE and in the brains of persons with PMS. These T cells also expressed the transcription factor Hobit in mice with chronic EAE. Single-cell transcriptomic analysis uncovered the transcriptional heterogeneity and inflammatory potential of CD4⁺ Trm cells, and, accordingly, these cells localized within CNS inflammatory lesions of mice with EAE and persons with PMS. Last, either genetic or pharmacological depletion of CD4⁺ Trm cells combined with antibody-mediated depletion of the recirculating CD4⁺ T cell compartment alleviated neurological signs during the chronic phase of EAE. Our results indicate that CD4⁺ Trm cells contribute to maintain a chronic inflammatory state in the CNS and suggest that therapeutic strategies for PMS should consider targeting the CNS-resident T cell compartment.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 808","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684779","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":"Protective envelope dimer epitope–like antibodies are elicited against dengue virus in children after infection and vaccination","authors":"Patrick I. Mpingabo,&nbsp;Michelle Ylade,&nbsp;Rosemary A. Aogo,&nbsp;Maria Vinna Crisostomo,&nbsp;Devina J. Thiono,&nbsp;Jedas Veronica Daag,&nbsp;Kristal-An Agrupis,&nbsp;Ana Coello Escoto,&nbsp;Guillermo L. Raimundi-Rodriguez,&nbsp;Camila D. Odio,&nbsp;Maria Abad Fernandez,&nbsp;Laura White,&nbsp;Aravinda M. de Silva,&nbsp;Jacqueline Deen,&nbsp;Leah C. Katzelnick","doi":"10.1126/scitranslmed.adq0571","DOIUrl":"10.1126/scitranslmed.adq0571","url":null,"abstract":"<div >Cross-reactive antibodies to epitopes that span envelope proteins on the virion surface are hypothesized to protect against dengue virus (DENV) infection and disease. Here, we measured antibodies targeting a quaternary epitope called the envelope dimer epitope (EDE) as well as neutralizing and binding antibodies and evaluated their association with DENV infection, vaccine response, and disease outcome in dengue-vaccinated (<i>n</i> = 164) and dengue-unvaccinated children (<i>n</i> = 88) within a longitudinal cohort in Cebu, Philippines (<i>n</i> = 2996). Antibodies targeting EDE were prevalent and associated with broad neutralization of mature DENV1 to DENV4 virions in those with evidence of at least two prior DENV infections but were mostly absent in those with only one prior infection. Subsequent infection and vaccination boosted titers of EDE-like antibodies, neutralizing antibodies, and DENV-binding antibodies. EDE-like antibodies were associated with reduced risk of symptomatic dengue and more severe dengue and statistically explained the protective effect of binding and neutralizing antibodies on dengue. Thus, antibodies targeting quaternary epitopes help explain the broad cross-protection observed in those with multiple prior DENV exposures, making them useful for evaluation and development of future vaccines and therapeutics.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 808","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685055","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":"Erratum for the Research Article “Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence” by A. Katsarou et al.","authors":"","doi":"10.1126/scitranslmed.aea1242","DOIUrl":"10.1126/scitranslmed.aea1242","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 808","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688287","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":"Systemic administration of an RNA binding and cell-penetrating antibody targets therapeutic RNA to multiple mouse models of cancer","authors":"Elias Quijano,&nbsp;Diana Martinez-Saucedo,&nbsp;Zaira Ianniello,&nbsp;Natasha Pinto-Medici,&nbsp;Madison Rackear,&nbsp;Haoting Chen,&nbsp;Luiz Lola-Pereira,&nbsp;Yanfeng Liu,&nbsp;Denise Hegan,&nbsp;Xinning Shan,&nbsp;Robert Tseng,&nbsp;Deanne Yugawa,&nbsp;Sumedha Chowdhury,&nbsp;Minsoo Khang,&nbsp;Jay P. Singh,&nbsp;Rashed Abdullah,&nbsp;Perisa Azhir,&nbsp;Soki Kashima,&nbsp;Wendy S. Woods,&nbsp;Nicholas Gosstola,&nbsp;Bruce C. Turner,&nbsp;Stephen Squinto,&nbsp;Dale L. Ludwig,&nbsp;Ranjit S. Bindra,&nbsp;Marie E. Robert,&nbsp;David A. Braun,&nbsp;Pablo Perez Pinera,&nbsp;W. Mark Saltzman,&nbsp;Luisa F. Escobar-Hoyos,&nbsp;Peter M. Glazer","doi":"10.1126/scitranslmed.adk1868","DOIUrl":"10.1126/scitranslmed.adk1868","url":null,"abstract":"<div >There is intense interest in the advancement of RNAs as rationally designed therapeutic agents, especially in oncology, where a major focus is to use RNAs to stimulate pattern recognition receptors to leverage innate immune responses. However, the inability to selectively deliver therapeutic RNAs within target cells after intravenous administration now hinders the development of this type of treatment for cancer and other disorders. Here, we found that a tumor-targeting, cell-penetrating, and RNA binding monoclonal antibody, TMAB3, can form stable, noncovalent antibody/RNA complexes of a discrete size that mediate highly specific and functional delivery of RNAs into tumors. Using 3p-hpRNA, an agonist of the pattern recognition receptor retinoic acid–inducible gene-I (RIG-I), we observed robust antitumor efficacy of systemically administered TMAB3/3p-hpRNA complexes in mouse models of pancreatic cancer, medulloblastoma, and melanoma. In the KPC syngeneic, orthotopic pancreatic cancer model in immunocompetent mice, treatment with TMAB3/3p-hpRNA tripled animal survival, decreased tumor growth, and specifically targeted malignant cells, with a 1500-fold difference in RNA delivery into tumor cells versus nonmalignant cells within the tumor mass. Single-cell RNA sequencing (scRNA-seq) and flow cytometry demonstrated that TMAB3/3p-hpRNA treatment elicited a potent antitumoral immune response characterized by RIG-I activation and increased infiltration and activity of cytotoxic T cells. These studies established that TMAB3/RNA complexes can deliver RNA payloads specifically to hard-to-treat tumor cells to achieve antitumor efficacy, providing an antibody-based platform to advance the study of RNA therapies for the treatment of patients with cancer.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 807","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640498","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 SIRT2 induces MLH1 deficiency and boosts antitumor immunity in preclinical colorectal cancer models","authors":"Qianling Gao,&nbsp;Lanlan Yang,&nbsp;Shubiao Ye,&nbsp;Mingru Mai,&nbsp;Yiting Liu,&nbsp;Xuefei Jiang,&nbsp;Xingzhi Feng,&nbsp;Zihuan Yang","doi":"10.1126/scitranslmed.adv0766","DOIUrl":"10.1126/scitranslmed.adv0766","url":null,"abstract":"<div >Low tumor mutation burden and an immunosuppressive tumor microenvironment (TME) of colorectal cancers (CRCs) contribute to resistance to immune-checkpoint inhibitors in patients. Understanding the mechanisms of cancer immune evasion will be helpful to develop new therapeutic strategies. Here, leveraging mass spectrometry–based proteomic profiling data and clinical validation, we identified that low sirtuin 2 (SIRT2) expression was associated with improved prognosis and an immune-active TME in CRC. Specifically, genetic knockdown or pharmacological inhibition of SIRT2 resulted in enhanced infiltration and cytotoxicity of CD8⁺ T cells, leading to tumor regression across multiple CRC mouse models and patient-derived organoids. Further in vitro experimental analysis demonstrated that SIRT2 interacted with and deacetylated MutL protein homolog 1 (MLH1) at Lys^402/443/461, thereby preventing MLH1 ubiquitination and degradation. SIRT2 knockdown or inhibition down-regulated MLH1, increasing DNA damage and activating the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway. In addition, both in vivo and in vitro experiments indicated that SIRT2 inhibition stimulated the production of tumor neoantigens and enhanced major histocompatibility complex class I (MHC-I) expression, reprogramming the TME toward an immune-active status and inducing long-lasting immune memory. Last, a combination strategy using SIRT2 inhibitor 2-cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide (AGK2) and anti–programmed cell death protein–1 (PD-1) therapy enhanced immune response, making tumors susceptible to immunotherapy and driving substantial tumor regression in vivo. Our study uncovers a role of SIRT2 in reprogramming TME and underscores the potential of targeting SIRT2 to sensitize CRC to immunotherapy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 807","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640550","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":"Complement is activated in patients with acute chest syndrome caused by sickle cell disease and represents a therapeutic target","authors":"Satheesh Chonat,&nbsp;Jayre A. Jones,&nbsp;Seema R. Patel,&nbsp;William M. Briones,&nbsp;Michelle L. Schoettler,&nbsp;Maya Maarouf,&nbsp;Lauren A. Jeffers,&nbsp;Olufolake Adisa,&nbsp;Fang Tan,&nbsp;Earl Fields,&nbsp;Morgan S. Sterling,&nbsp;Ryan P. Jajosky,&nbsp;Hans Verkerke,&nbsp;Sara H. Graciaa,&nbsp;Elisabetta M. Foppiani,&nbsp;Ross M. Fasano,&nbsp;Patricia E. Zerra,&nbsp;Yongzhi Qiu,&nbsp;Connie M. Arthur,&nbsp;Wilbur A. Lam,&nbsp;Solomon F. Ofori-Acquah,&nbsp;Michael Koval,&nbsp;Clinton H. Joiner,&nbsp;David R. Archer,&nbsp;Sean R. Stowell","doi":"10.1126/scitranslmed.adl4922","DOIUrl":"10.1126/scitranslmed.adl4922","url":null,"abstract":"<div >Despite being the first genetic disease described, sickle cell disease (SCD) continues to result in severe complications. Of these complications, acute chest syndrome (ACS), a form of acute lung injury, leads all-cause mortality. However, the pathophysiology of ACS remains incompletely understood, resulting in patients with ACS receiving only supportive measures. Here, we found that ACS is accompanied by activation of the complement pathway, an evolutionarily ancient innate immune system responsible for eliminating microbes. Using a well-defined preclinical model of SCD, hemolysis, a precursor of ACS, not only induced ACS but also drove robust complement activation. Artificial activation of complement alone similarly induced ACS, whereas genetic removal or pharmacological inhibition of complement rendered SCD mice resistant to ACS even after induction of hemolysis. These results demonstrate that complement drives ACS, establishing a link between SCD and this ancient form of immunity that provides an opportunity for targeted treatment of this complication.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 807","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640586","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}