Science Translational Medicine最新文献

{"title":"USP5 inhibition enables potential therapy for t(8;21) AML through ubiquitin-mediated AML1-ETO degradation in patient-derived xenografts","authors":"Lan Ma,&nbsp;Kun Zhang,&nbsp;Zixuan Zhang,&nbsp;Chenyang Wang,&nbsp;Mengyuan Ma,&nbsp;Ying Liu,&nbsp;Yanli Zhao,&nbsp;Ziqing Gong,&nbsp;Ning Liu,&nbsp;Mingming Wei,&nbsp;Xiang Liu,&nbsp;Jingfeng Zhou,&nbsp;Shuangwei Liu,&nbsp;Cheng Yang,&nbsp;Guang Yang","doi":"10.1126/scitranslmed.adt9100","DOIUrl":"10.1126/scitranslmed.adt9100","url":null,"abstract":"<div >The AML1-ETO (AE) fusion protein is a key target for treating t(8;21) acute myeloid leukemia (AML). In this investigation, we identified ubiquitin-specific protease 5 (USP5) as the deubiquitinating enzyme of AE. USP5 knockdown decreased AML cell growth and induced differentiation both in vitro and in vivo. In addition, we developed a high-throughput screening (HTS) method and identified a potent, selective USP5 inhibitor, WCY-8-67. This lead compound was identified as a selective USP5 inhibitor by targeting the ubiquitin-associated domain 2 (UBA2) region. It also induced aggregation and precipitation of the target protein, which led to USP5 dysfunction. WCY-8-67 exhibited excellent in vivo bioavailability and tolerability, and it effectively inhibited the growth of AML cells in animal models. In addition, in a patient-derived xenograft (PDX) model, this compound, when combined with 5-azacytidine (5-Aza), improved therapeutic effects. This study presents promising targeted therapeutic possibilities for the treatment of t(8;21) AML that require further study.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 817","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129560","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":"Progression to rheumatoid arthritis in at-risk individuals is defined by systemic inflammation and by T and B cell dysregulation","authors":"Ziyuan He,&nbsp;Marla C. Glass,&nbsp;Pravina Venkatesan,&nbsp;Marie L. Feser,&nbsp;Leander Lazaro,&nbsp;Lauren Y. Okada,&nbsp;Nhung T. T. Tran,&nbsp;Yudong D. He,&nbsp;Samir Rachid Zaim,&nbsp;Christy E. Bennett,&nbsp;Padmapriyadarshini Ravisankar,&nbsp;Elisabeth M. Dornisch,&nbsp;Alexandra C. Ferrannini,&nbsp;Najeeb A. Arishi,&nbsp;Ashley G. Asamoah,&nbsp;Saman Barzideh,&nbsp;Lynne A. Becker,&nbsp;Elizabeth A. Bemis,&nbsp;Jane H. Buckner,&nbsp;Christopher E. Collora,&nbsp;Megan A. L. Criley,&nbsp;M. Kristen Demoruelle,&nbsp;Chelsie L. Fleischer,&nbsp;Jessica Garber,&nbsp;Palak C. Genge,&nbsp;Qiuyu Gong,&nbsp;Lucas T. Graybuck,&nbsp;Claire E. Gustafson,&nbsp;Brian C. Hattel,&nbsp;Veronica Hernandez,&nbsp;Alexander T. Heubeck,&nbsp;Erin K. Kawelo,&nbsp;Upaasana Krishnan,&nbsp;Emma L. Kuan,&nbsp;Kristine A. Kuhn,&nbsp;Christian M. LaFrance,&nbsp;Kevin J. Lee,&nbsp;Ruoxin Li,&nbsp;Cara Lord,&nbsp;Regina R. Mettey,&nbsp;Laura Moss,&nbsp;Blessing Musgrove,&nbsp;Katherine HY Nguyen,&nbsp;Andrea Ochoa,&nbsp;Vaishnavi Parthasarathy,&nbsp;Mark-Phillip Pebworth,&nbsp;Chong Pedrick,&nbsp;Tao Peng,&nbsp;Cole G. Phalen,&nbsp;Julian Reading,&nbsp;Charles R. Roll,&nbsp;Jennifer A. Seifert,&nbsp;Marguerite D. Siedschlag,&nbsp;Cate Speake,&nbsp;Christopher C. Striebich,&nbsp;Tyanna J. Stuckey,&nbsp;Elliott G. Swanson,&nbsp;Hideto Takada,&nbsp;Tylor Thai,&nbsp;Zachary J. Thomson,&nbsp;Nguyen Trieu,&nbsp;Vlad Tsaltskan,&nbsp;Wei Wang,&nbsp;Morgan D. A. Weiss,&nbsp;Amy Westermann,&nbsp;Fan Zhang,&nbsp;David L. Boyle,&nbsp;Ananda W. Goldrath,&nbsp;Thomas F. Bumol,&nbsp;Xiao-jun Li,&nbsp;V. Michael Holers,&nbsp;Peter J. Skene,&nbsp;Adam K. Savage,&nbsp;Gary S. Firestein,&nbsp;Kevin D. Deane,&nbsp;Troy R. Torgerson,&nbsp;Mark A. Gillespie","doi":"10.1126/scitranslmed.adt7214","DOIUrl":"10.1126/scitranslmed.adt7214","url":null,"abstract":"<div >Rheumatoid arthritis (RA) is preceded by an at-risk stage of disease that can be marked by the presence of anticitrullinated protein antibodies (ACPAs) but the absence of clinically apparent synovitis (clinical RA). Preemptive intervention in at-risk individuals could prevent or delay future tissue damage; however, the immunobiology of this stage is unclear. Using integrative multiomics, we longitudinally profiled at-risk individuals, where one-third of participants developed clinical RA on study. We found evidence of systemic inflammation and signatures of activation in naïve T and B cells of at-risk individuals. During progression to clinical RA, proinflammatory skewing of atypical B cells and expansion of memory CD4 T cells with signatures of activation and B cell help were present without elevations in circulating ACPA titers. Epigenetic changes in naïve CD4 T cells suggested a predisposition to differentiate into effector cells capable of B cell help. These findings characterize pathogenesis of the ACPA⁺ at-risk stage and support the concept that the disease begins much earlier than clinical RA. Additionally, an extensive immune resource of the at-risk stage and progression to clinical RA with interactive tools was developed to enable further investigation.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 817","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adt7214","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129539","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":"Erratum for the Research Article “An oral heme oxygenase inhibitor targets immunosuppressive perivascular macrophages in preclinical models of cancer” by M. Bahri et al.","authors":"","doi":"10.1126/scitranslmed.aec0154","DOIUrl":"10.1126/scitranslmed.aec0154","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 817","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129563","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":"A complete Sigmodon hispidus genome and dynamic single-cell transcriptomics reveal evolutionarily conserved responses to RSV infection","authors":"Shijie Qin,&nbsp;Xiao Qu,&nbsp;Chao Lv,&nbsp;Yali Hou,&nbsp;Xiaoyan Li,&nbsp;Fei Ma,&nbsp;Shuguang Tan,&nbsp;Kefang Liu,&nbsp;Ye Yin,&nbsp;Yi Jing,&nbsp;Xuancheng Lu,&nbsp;Xin Zhao,&nbsp;Xiaopeng Ma,&nbsp;George Fu Gao","doi":"10.1126/scitranslmed.adw7535","DOIUrl":"10.1126/scitranslmed.adw7535","url":null,"abstract":"<div >The cotton rat (<i>Sigmodon hispidus</i>) has emerged as a preclinical model for human respiratory syncytial virus (RSV) research because of its ability to support effective viral replication and recapitulate disease; however, the mechanisms supporting this evolutionarily conserved phenotype remain unclear. Here, we report both the chromosomal genome and respiratory single-cell transcriptomic atlas of the cotton rat throughout the course of RSV infection. Phylogenetic analysis showed that cotton rats are in different evolutionary branches from common mouse and rat models and exhibit substantial conservation of tissue profiles with humans. The respiratory cell atlas, alveolar cell trajectory, and distribution of potential viral receptors are also similar to those of humans, explaining the superiority of cotton rats as an RSV infection model. The target cells of RSV, including club cells, secretory2 cells, mesothelial cells, and nerve-associated astrocytes, were expanded after infection. We also identified differential transcriptional regulators, specific antiviral proteins, and cytokines that could be translated into potential clinical markers in humans. Candidate host factors were also identified, which will enable the exploration of host-RSV interactions and offer a source of therapeutic targets.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 816","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077452","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":"Sex differences in HIV-1 reservoir cell selection are linked to altered innate immune profiles","authors":"Toong Seng Tan,&nbsp;Ce Gao,&nbsp;Alexander S. Hochroth,&nbsp;Liliana Vela,&nbsp;Leah Carrere,&nbsp;Sruthi Kalavacherla,&nbsp;Seohyun Hong,&nbsp;Melanie Lancien,&nbsp;Chloe M. Naasz,&nbsp;Aischa Niesar,&nbsp;Samantha K. Marzi,&nbsp;Isabelle C. Roseto,&nbsp;Benjamin Bone,&nbsp;Xiaodong Lian,&nbsp;Yuko Yuki,&nbsp;Mathias Viard,&nbsp;Rebecca Hoh,&nbsp;Deborah K. McMahon,&nbsp;Ronald J. Bosch,&nbsp;Seble G. Kassaye,&nbsp;Rajesh T. Gandhi,&nbsp;Mary Carrington,&nbsp;Steven G. Deeks,&nbsp;Phyllis C. Tien,&nbsp;Michael J. Peluso,&nbsp;Jeffrey M. Jacobson,&nbsp;Mathias Lichterfeld,&nbsp;Xu G. Yu","doi":"10.1126/scitranslmed.adu7154","DOIUrl":"10.1126/scitranslmed.adu7154","url":null,"abstract":"<div >HIV-1 persistence despite suppressive antiretroviral therapy (ART) is primarily because of infected memory CD4 T cells, so-called viral reservoir cells, that harbor chromosomally integrated viral DNA as a “provirus” and resist clearance by the human immune system. Biological sex affects host immune responses and may influence selection and evolution of HIV-1 reservoir cells during long-term ART for HIV infection. We assessed more than 4073 individual proviruses through single-molecule amplification from 30 females and 35 males living with HIV-1 and treated with ART for a median of 20 years. We observed that the HIV-1 reservoir profile in females was characterized by lower proviral phylogenetic complexity, an increased proportion of clonally expanded intact proviruses, and a higher proportion of intact proviruses integrated into repressive heterochromatin locations of the human genome. The evolution of this distinct viral reservoir profile in females was associated with an improved signature of innate immune responses, specifically those of NK cells. On the contrary, signs of viral sequence adaptation to adaptive T cell immune responses were more pronounced in intact HIV-1 proviruses from males. Collectively, these data suggest a stronger ability of the female immune system to drive immune selection of HIV-1 reservoir cells during ART, putatively because of improved innate immune function.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 816","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077450","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":"PD-1–targeted cis-delivery of an IL-2 variant induces a multifaceted antitumoral T cell response in human lung cancer","authors":"Irene Fusi,&nbsp;Clara Serger,&nbsp;Petra Herzig,&nbsp;Markus Germann,&nbsp;Michael T. Sandholzer1,&nbsp;Nicole Oelgarth1,&nbsp;Petra C. Schwalie,&nbsp;Leyla Don,&nbsp;Viola K. Vetter,&nbsp;Viktor H. Koelzer,&nbsp;Didier Lardinois,&nbsp;Henry Kao,&nbsp;Laura Codarri Deak,&nbsp;Pablo Umaña,&nbsp;Christian Klein,&nbsp;Aljaz Hojski,&nbsp;Marina Natoli,&nbsp;Alfred Zippelius","doi":"10.1126/scitranslmed.adr3718","DOIUrl":"10.1126/scitranslmed.adr3718","url":null,"abstract":"<div >Antibody-cytokine fusion proteins are being developed as next-generation cancer immunotherapies, aiming to deliver activation signals to targeted immune populations. Among these, PD1-IL2v—an engineered interleukin-2 variant (IL-2v) lacking CD25 binding, fused to a high-affinity programmed cell death protein 1 (PD-1) blocking antibody—has shown promising results in murine tumor models. Here, using human model systems, we show that PD1-IL2v elicits a multifaceted antitumor T cell response by targeting both CD8⁺ and conventional CD4⁺ T (T_conv) cells. Single-cell RNA sequencing (scRNAseq) on a lung cancer patient–derived tumor fragment (PDTF) platform revealed that PD1-IL2v drives the expansion of proliferative, cytotoxic CD8⁺ T cells exhibiting features of tumor reactivity. This was accompanied by up-regulation of CXCR6, enhancing their migratory capacity. In T_conv cells, PD1-IL2v up-regulated CXCL13 expression and promoted a T follicular helper/T helper 1 (T_FH/T_H1)–like transcriptional program associated with anti-PD1 responsiveness. Our findings provide mechanistic insights into the effects of IL-2v–targeted delivery to PD-1⁺ cells within human tumors, supporting the clinical development of next-generation immunocytokines.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 816","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077451","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":"Longitudinal antibody titers measured after COVID-19 mRNA vaccination can identify individuals at risk for subsequent infection","authors":"Hyeongki Park,&nbsp;Naotoshi Nakamura,&nbsp;Sho Miyamoto,&nbsp;Yoshitaka Sato,&nbsp;Kwang Su Kim,&nbsp;Kosaku Kitagawa,&nbsp;Yurie Kobashi,&nbsp;Yuta Tani,&nbsp;Yuzo Shimazu,&nbsp;Tianchen Zhao,&nbsp;Yoshitaka Nishikawa,&nbsp;Fumiya Omata,&nbsp;Moe Kawashima,&nbsp;Toshiki Abe,&nbsp;Yoshika Saito,&nbsp;Saori Nonaka,&nbsp;Morihito Takita,&nbsp;Chika Yamamoto,&nbsp;Hiroshi Morioka,&nbsp;Katsuhiro Kato,&nbsp;Ken Sagou,&nbsp;Tetsuya Yagi,&nbsp;Takeshi Kawamura,&nbsp;Akira Sugiyama,&nbsp;Aya Nakayama,&nbsp;Yudai Kaneko,&nbsp;Risa Yokokawa Shibata,&nbsp;Kazuyuki Aihara,&nbsp;Tatsuhiko Kodama,&nbsp;Akifumi Kamiyama,&nbsp;Tomokazu Tamura,&nbsp;Takasuke Fukuhara,&nbsp;Kenji Shibuya,&nbsp;Tadaki Suzuki,&nbsp;Shingo Iwami,&nbsp;Masaharu Tsubokura","doi":"10.1126/scitranslmed.adv4214","DOIUrl":"10.1126/scitranslmed.adv4214","url":null,"abstract":"<div >A key issue in the post–COVID-19 pandemic era is the ongoing administration of COVID-19 vaccines. Repeated vaccination is essential for preparing against currently circulating and newly emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. However, optimizing vaccination strategies is crucial to efficiently manage medical resources and establish an effective vaccination framework. Therefore, a strategy to identify poor responders with lower sustained antibody titers would be beneficial because these individuals should be considered high priority for revaccination. We investigated longitudinal antibody titer data in a cohort of 2526 people in Fukushima, Japan, collected between April 2021 and November 2022. Using mathematical modeling and machine learning, we stratified the time-course patterns of antibody titers after two primary doses and one booster dose of COVID-19 messenger RNA vaccines. We identified three populations, which we refer to as the durable, the vulnerable, and the rapid-decliner populations, and approximately half of the participants remained in the same population after the booster dose. The rapid-decliner population experienced earlier infections than the others. Furthermore, when comparing spike protein–specific immunoglobulin G (IgG) titers, spike protein–specific IgA titers, and SARS-CoV-2–specific T cell responses between participants who experienced subsequent infections after booster vaccination and those who did not, we found that spike protein–specific IgA titers were lower during the early stage after booster vaccination in participants who went on to become infected with SARS-CoV-2. This approach could be used to inform policy decisions on vaccine distribution to maximize population-level immunity both in future pandemics and in the post–COVID-19 pandemic era.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 816","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adv4214","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077454","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":"Hippocampal spreading depolarization as a driver of postictal ambulation","authors":"Bence Mitlasóczki,&nbsp;Adrián Gutiérrez Gómez,&nbsp;Midia Kamali,&nbsp;Natalia Babushkina,&nbsp;Mayan Baues,&nbsp;Laura Kück,&nbsp;André Nathan Haubrich,&nbsp;Theodoros Tamiolakis,&nbsp;Annika Breuer,&nbsp;Simon Granak,&nbsp;Merlin Schwering-Sohnrey,&nbsp;Ingo Gerhauser,&nbsp;Wolfgang Baumgärtner,&nbsp;Martin Karl Schwarz,&nbsp;Laura Ewell,&nbsp;Thoralf Opitz,&nbsp;Julika Pitsch,&nbsp;Simon Musall,&nbsp;Rainer Surges,&nbsp;Florian Mormann,&nbsp;Heinz Beck,&nbsp;Michael Wenzel","doi":"10.1126/scitranslmed.adv3260","DOIUrl":"10.1126/scitranslmed.adv3260","url":null,"abstract":"<div >Postseizure (postictal) symptoms are regularly encountered in epilepsy and can be life threatening, yet their neurobiological underpinnings remain understudied. Using two-photon or widefield imaging, field potential and unit recordings, optogenetics, and basic behavioral assessment under healthy conditions or viral encephalitis, we studied seizures and postictal symptoms in mice. We show a propensity of the hippocampus for seizure-associated spreading depolarization (sSD). Through optogenetic stimulation, we provide evidence that induced isolated hippocampal SD is sufficient to elicit postictal ambulation (PIA), whereas induced isolated seizure-like episodes are not. Furthermore, PIA occurred in the absence of SD progression to the neocortex. In addition, we analyzed Behnke-Fried depth-electrode recordings in four patients with focal epilepsy. Of 13 recorded seizures, we observed five slow shifts at seizure termination in the regionwise analysis that could reflect putative sSD. In support of our experiments in mice, we also found an increased vulnerability of the human temporomesial system (hippocampus and amygdala) for this phenomenon and longer recovery times of affected as compared with nonaffected brain regions. This work suggests sSD as a previously underrecognized pathoclinical entity underlying distinct postictal symptoms in epilepsy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 816","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077455","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":"Export by a quorum sensing–controlled drug exporter underlies rifampicin’s strong activity against staphylococcal biofilms","authors":"Yao Liu,&nbsp;Lei He,&nbsp;Ryan Liu,&nbsp;Dylan J. Burgin,&nbsp;Min Li,&nbsp;Michael Otto","doi":"10.1126/scitranslmed.adq8328","DOIUrl":"10.1126/scitranslmed.adq8328","url":null,"abstract":"<div >Biofilm infections on indwelling medical devices are a major cause of health care–associated infection and mortality. Most of these infections are caused by staphylococci. Biofilm formation presents a continued clinical challenge because of the association with dramatically increased nonspecific antimicrobial resistance. Unlike most antibiotics, rifampicin is active against staphylococcal biofilm infections; however, the mechanism is unknown. Using in vitro assays and mouse models of biofilm infection, we show here that rifampicin is more effective than other antibiotics against staphylococcal <i>agr</i> mutants, which are linked to serious biofilm infections because they produce extended biofilms. We found that this superiority results from an Agr-controlled rifampicin efflux system, which makes <i>agr</i> mutant biofilms less resistant to rifampicin, rather than more resistant, than they are to other antibiotics. Our study provides a scientific rationale supporting the use of rifampicin in staphylococcal biofilm infections and emphasizes the importance of understanding genetic adaptations during infection for the use and development of biofilm therapeutics.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 816","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077453","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":"Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis","authors":"Hongxue Shi,&nbsp;Xiaobo Wang,&nbsp;Christopher Sloas,&nbsp;Brennan Gerlach,&nbsp;Arif Yurdagul Jr.,&nbsp;Mary P. Moore,&nbsp;Eui Jung Jung,&nbsp;Faridoddin Mirshahi,&nbsp;Luisa Ronzoni,&nbsp;Arun J. Sanyal,&nbsp;Luca Valenti,&nbsp;Chyuan-Sheng Lin,&nbsp;James Montgomery,&nbsp;Bradley Zinker,&nbsp;Michael Klichinsky,&nbsp;Ira Tabas","doi":"10.1126/scitranslmed.adv2106","DOIUrl":"10.1126/scitranslmed.adv2106","url":null,"abstract":"<div >Hepatocyte apoptosis is a key feature of metabolic dysfunction–associated steatohepatitis (MASH), but the fate of apoptotic hepatocytes in MASH is poorly understood. Here, we explore the hypotheses that clearance of dead hepatocytes by liver macrophages (efferocytosis) is impaired in MASH because of low expression of the efferocytosis receptor T cell immunoglobulin and mucin domain containing 4 (TIM4; gene <i>Timd4</i>) by MASH liver macrophages, which then drives liver fibrosis in MASH. We show that apoptotic hepatocytes accumulate in human and experimental MASH, using mice fed the fructose-palmitate-cholesterol (FPC) diet or the high-fat, choline-deficient amino acid–defined (HF-CDAA) diet. Apoptotic hepatocyte accumulation is associated with impaired efferocytosis and loss of TIM4. Administration of neutralizing anti-TIM4 antibodies or genetic deletion of <i>Timd4</i> in Kupffer cells of FPC and HF-CDAA diet–fed mice decreased efferocytosis by liver macrophages, increased profibrotic activation of collagen-producing hepatic stellate cells (HSCs), and accelerated the progression to fibrotic MASH. Genetic restoration of macrophage <i>Timd4</i> in FPC and HF-CDAA diet–fed MASH mice or cell therapy with TIM4⁺ macrophages enhanced apoptotic hepatocyte clearance and decreased HSC activation and liver fibrosis. Studies using an ex vivo macrophage HSC cross-talk model and the HF-CDAA MASH model revealed that inactivation of HSCs by efferocytosing macrophages involved macrophage reprogramming to secrete interleukin-10 (IL-10), which activated the IL-10 receptor on HSCs to dampen their profibrotic activation. These findings reveal a key process in the progression from hepatic steatosis to early MASH fibrosis and identify a mechanism-based therapeutic strategy to prevent fibrotic MASH progression.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 815","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028489","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}