Signal Transduction and Targeted Therapy最新文献

{"title":"Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation","authors":"Dan-Yun Ruan, Hao-Xiang Wu, Ye Xu, Pamela N. Munster, Yanhong Deng, Gary Richardson, Dong Yan, Myung-Ah Lee, Keun-Wook Lee, Hongming Pan, Steven Hager, Xingya Li, Shaozhong Wei, Xinfang Hou, Craig Underhill, Michael Millward, Ina Nordman, Jingdong Zhang, Jianzhen Shan, Guohong Han, Jaspreet Grewal, Shirish M. Gadgeel, Rachel E. Sanborn, Seok Jae Huh, Xiaohua Hu, Yihong Zhang, Ziyong Xiang, Laisheng Luo, Xiaoxi Xie, Zhe Shi, Yaolin Wang, Ling Zhang, Feng Wang, Rui-Hua Xu","doi":"10.1038/s41392-025-02274-z","DOIUrl":"https://doi.org/10.1038/s41392-025-02274-z","url":null,"abstract":"<p>Mutations in the KRAS gene have long been implicated in the pathogenesis of colorectal cancer (CRC). KRAS G12C inhibitors overcome the “undruggable” challenge, enabling precision therapy. Garsorasib (D-1553), a highly potent and selective KRAS G12C inhibitor, has demonstrated promising anti-tumor activity and favorable safety profile in early clinical trials. We conducted an open-label, nonrandomized phase II trial (ClinicalTrials.gov, NCT04585035) to assess the safety and efficacy of garsorasib with or without cetuximab in KRAS G12C-mutated CRC. In the monotherapy cohort (n = 26), objective response rate (ORR) was 19.2% (95% CI, 6.6–39.4), disease control rate (DCR) was 92.3% (95% CI, 74.9–99.1), median progression-free survival (PFS) was 5.5 months (95% CI, 2.9–11.6) and median overall survival (OS) was 13.1 months (95% CI, 9.5-NE). In the combination cohort (n = 42), ORR was 45.2% (95% CI, 29.8–61.3), DCR was 92.9% (95% CI, 80.5–98.5), median PFS was 7.5 months (95% CI, 5.5–8.1), and median OS was not reached. Grade ≥3 treatment-related adverse events occurred in 5 (19.2%) and 6 (14.3%) patients in monotherapy and combination cohort, respectively. Garsorasib with or without cetuximab showed a promising efficacy and manageable safety profiles in heavily pretreated patients with KRAS G12C-mutated CRC, providing a potential new treatment approach for such population.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"13 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144304720","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":"Purine nucleoside phosphorylase dominates Influenza A virus replication and host hyperinflammation through purine salvage","authors":"Yang Yue, Qingyu Li, Changguo Chen, Juntao Yang, Weian Song, Changdong Zhou, Yuke Cui, Zhenqiao Wei, Qi He, Chenhui Wang, Hongjun Lin, Jiangbo Li, Jian Li, Ji Xi, Xiang Song, Wen Yang, Ze Zhang, Wenjie Shu, Liang Guo, Shengqi Wang","doi":"10.1038/s41392-025-02272-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02272-1","url":null,"abstract":"<p>Influenza A virus (IAV) poses a significant threat to human health. The outcome of IAV results from the viral-host interaction, with the underlying molecular mechanisms largely unknown. By integrating the plasma proteomics data of the IAV-infected patients into the viral-inflammation protein-protein interaction (VI-PPI) network created in this study, purine nucleoside phosphorylase (PNP), the critical enzyme in purine salvage, was identified as a potential hub gene that connected the different stages of IAV infection. Extended survival rates and reduced pulmonary inflammatory lesions were observed in alveolar epithelial cell (AEC)-specific PNP conditional knockout mice upon H1N1 infection. Mechanistically, PB1-F2 of IAV was revealed as a novel viral transcriptional factor to bind to the TATA box of PNP promoter, leading to enhanced purine salvage in H1N1-challenged AECs. The activation of PNP-mediated purine salvage was verified in IAV-infected patients and A549 cells. PNP knockdown elicited a purine metabolic shift from augmented salvage pathway to de novo synthesis, constraining both viral infection and pro-inflammatory signaling through APRT-AICAR-AMPK activation. Moreover, durdihydroartemisinin (DHA), predicted by VI-PPI as a novel PNP inhibitor, exerted beneficial effects on the survival and weight gain of H1N1-challenged mice via its direct binding to PNP. To reveal for the first time, we found that PNP, activated by IAV, plays a hub role within H1N1-host interaction, simultaneously modulating viral replication and hyperinflammation through purine salvage. Our study sheds new light on a “two-for-one” strategy by targeting purine salvage in combating IAV-related pathology, suggesting PNP as a potential novel anti-influenza host target.</p><figure></figure>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"22 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290096","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":"Advances in molecular pathology and therapy of non-small cell lung cancer","authors":"Qing Huang, Yuanxiang Li, Yingdan Huang, Jingyi Wu, Wendai Bao, Chang Xue, Xiaoyu Li, Shuang Dong, Zhiqiang Dong, Sheng Hu","doi":"10.1038/s41392-025-02243-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02243-6","url":null,"abstract":"<p>Over the past two decades, non-small cell lung cancer (NSCLC) has witnessed encouraging advancements in basic and clinical research. However, substantial unmet needs remain for patients worldwide, as drug resistance persists as an inevitable reality. Meanwhile, the journey towards amplifying the breadth and depth of the therapeutic effect requires comprehending and integrating diverse and profound progress. In this review, therefore, we aim to comprehensively present such progress that spans the various aspects of molecular pathology, encompassing elucidations of metastatic mechanisms, identification of therapeutic targets, and dissection of spatial omics. Additionally, we also highlight the numerous small molecule and antibody drugs, encompassing their application alone or in combination, across later-line, frontline, neoadjuvant or adjuvant settings. Then, we elaborate on drug resistance mechanisms, mainly involving targeted therapies and immunotherapies, revealed by our proposed theoretical models to clarify interactions between cancer cells and a variety of non-malignant cells, as well as almost all the biological regulatory pathways. Finally, we outline mechanistic perspectives to pursue innovative treatments of NSCLC, through leveraging artificial intelligence to incorporate the latest insights into the design of finely-tuned, biomarker-driven combination strategies. This review not only provides an overview of the various strategies of how to reshape available armamentarium, but also illustrates an example of clinical translation of how to develop novel targeted drugs, to revolutionize therapeutic landscape for NSCLC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"623 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290090","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":"Dual ENPP1/ATM depletion blunts DNA damage repair boosting radioimmune efficacy to abrogate triple-negative breast cancer","authors":"Borja Ruiz-Fernández de Córdoba, Karmele Valencia, Connor Welch, Haritz Moreno, Susana Martínez-Canarias, Carolina Zandueta, Eduardo Gómez, Alfonso Calvo, Nerea Otegui, Mirari Echepare, Ignacio Garzón, Daniel Ajona, David Lara-Astiaso, Elisabeth Guruceaga, Laura Guembe, Rubén Pío, Ignacio Melero, Silve Vicent, Fernando Pastor, Rafael Martínez-Monge, Fernando Lecanda","doi":"10.1038/s41392-025-02271-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02271-2","url":null,"abstract":"<p>The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer (TNBC), primarily by contributing to tumor cell survival and treatment resistance. However, the precise mechanisms remain unclear. In a model of local recurrence (LR), circulating tumor cells (CTC) engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1⁺-gene signature which was also identified in TNBC patients, suggesting ENPP1´s role in genome integrity. Blockade of ENPP1 using a permeable ENPP1 inhibitor (AVA-NP-695) reduced radioresistance, mechanistically attributed to decreased homologous recombination (HR) resulting in persistent DNA damage, as evidenced by enhanced tail moment and sustained γH2AX formation. This impaired DNA damage repair (DDR) sensitized tumor cells to ionizing radiation (IR). Notably, several DDR inhibitors (i) (including PARPi and ATMi) showed the highest synergy score in a targeted pharmacological screening. In vivo, dual ENPP1/ATM inhibition heightened radiosensitivity, compromised tumor cell survival and enhanced STING-TBK1 signaling by preventing ENPP1-mediated cGAMP hydrolysis. This resulted in robust innate and long-lasting adaptive antitumor immune memory responses, leading to significant tumor regression. Remarkably, combined treatment post-IR reduced spontaneous metastasis and local recurrence, and induced abscopal effects that impacted distant tumor spread in orthotopic tumor models. Thus, these findings position ENPP1 as a critical link between genome integrity and immunosuppression, offering promising translational opportunities for treating local or distant dissemination in TNBC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"42 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278413","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":"Stem loop binding protein promotes SARS-CoV-2 replication via -1 programmed ribosomal frameshifting","authors":"Tanxiu Chen, Ruimin Zhu, Tingfu Du, Hao Yang, Xintian Zhang, Zhixing Wang, Yong Zhang, Wenqi Quan, Bin Yin, Yunpeng Liu, Shuaiyao Lu, Xiaozhong Peng","doi":"10.1038/s41392-025-02277-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02277-w","url":null,"abstract":"<p>The -1 programmed ribosomal frameshifting (-1 PRF) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for keeping the balance between pp1a and pp1ab polyproteins. To date, the host factors influencing this process remain poorly understood. Using RNA pull-down assays combined with mass spectrometry screening, we discovered five host proteins interacting with -1 PRF RNA, including Stem Loop Binding Protein (SLBP). Our findings revealed that SLBP overexpression enhanced frameshifting and promoted viral replication. Moreover, the interaction between SLBP and -1 PRF RNA was predicted using the PrismNet deep learning tool, which calculated a high binding probability of 0.922. Using Electrophoretic Mobility Shift Assays (EMSAs) and RNA pull down assays, our findings demonstrated SLBP’s direct binding to the SARS-CoV-2 genome, with preferential affinity for the stem loop 3 region of the -1 PRF RNA. Using smFISH assays, we further confirmed their physical colocalization. The role of SLBP in promoting frameshifting was verified using an in vitro translation system. Further investigation showed that SLBP deletions reshaped the host factor pattern around -1 PRF RNA, diminishing interactions with FUBP3 and RPS3A while enhancing RPL10A binding. Together, our findings identify SLBP as a host protein that promotes SARS-CoV-2 frameshifting, highlighting its potential as a druggable target for COVID-19.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"51 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278651","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":"Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances","authors":"Xieyang Xu, Yan Pang, Xianqun Fan","doi":"10.1038/s41392-025-02253-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02253-4","url":null,"abstract":"<p>Mitochondria are the energy production centers in cells and have unique genetic information. Due to the irreplaceable function of mitochondria, mitochondrial dysfunction often leads to pathological changes. Mitochondrial dysfunction induces an imbalance between oxidation and antioxidation, mitochondrial DNA (mtDNA) damage, mitochondrial dynamics dysregulation, and changes in mitophagy. It results in oxidative stress due to excessive reactive oxygen species (ROS) generation, which contributes to cell damage and death. Mitochondrial dysfunction can also trigger inflammation through the activation of damage-associated molecular patterns (DAMPs), inflammasomes and inflammatory cells. Besides, mitochondrial alterations in the functional regulation, energy metabolism and genetic stability accompany the aging process, and there has been a lot of evidence suggesting that oxidative stress and inflammation, both of which are associated with mitochondrial dysfunction, are predisposing factors of aging. Therefore, this review hypothesizes that mitochondria serve as central hubs regulating oxidative stress, inflammation, and aging, and their dysfunction contributes to various diseases, including cancers, cardiovascular diseases, neurodegenerative disorders, metabolic diseases, sepsis, ocular pathologies, liver diseases, and autoimmune conditions. Moreover, we outline therapies aimed at various mitochondrial dysfunctions, highlighting their performance in animal models and human trials. Additionally, we focus on the limitations of mitochondrial therapy in clinical applications, and discuss potential future research directions for mitochondrial therapy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"4 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260477","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":"Limited but powerful toolbox: myeloid cells as critical immunomodulators in glioma progression","authors":"Yun Liu, Jincheng Fang, Roman Sankowski","doi":"10.1038/s41392-025-02275-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02275-y","url":null,"abstract":"<p>In their recent publication in Nature, Miller et al. studied recurrent transcriptional programs across various brain tumors. The authors identified four immunomodulatory expression programs in myeloid cells driven by factors within the tumor microenvironment (TME) including hypoxia, IL-1β, TGFβ, and dexamethasone treatment¹. Notably, the authors link clinical use of dexamethasone with an immunosuppressive myeloid program, potentially highlighting dexamethason’s compounding effect on glioblastoma-associated immunosuppression.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"218 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260576","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":"Mitsugumin 53 drives stem cell differentiation easing intestinal injury and inflammation","authors":"Yumeng Pei, Meng Fang, Hong-Kun Wu, Qionghua Cui, Li Quan, Xiaochuan Li, Keyi Zhang, Peng Xie, Peng Jiang, Yuan Liu, Meimei Huang, Fengxiang Lv, Xiaomin Hu, Ye-Guang Chen, Xinli Hu, Rui-Ping Xiao","doi":"10.1038/s41392-025-02268-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02268-x","url":null,"abstract":"<p>Emerging evidence suggests that priming intestinal stem cells (ISCs) towards secretory progenitor cells is beneficial for maintaining gut homeostasis against inflammatory bowel disease (IBD). However, the mechanism driving such biased lineage commitment remains elusive. Here we show that MG53, also named as TRIM72, prompts ISCs to secretory lineages via upregulating peroxisome proliferator-activated receptor α (PPARα), thus maintaining intestinal epithelium integrity against noxious insults. Using genetic mouse models, we found that MG53 deficiency leads to exacerbated intestinal damage caused by various injuries in mice, whereas MG53 overexpression in ISCs is sufficient to ameliorate such damage. Mechanistically, MG53 promoted asymmetric division of ISCs to generate more progenitor cells of secretory lineages via activating PPARα signaling. Specifically, MG53 overexpression induced PPARα expression at transcriptional level and concomitantly increased PPARα activity by elevating the contents of a panel of unsaturated fatty acids in the intestine that serve as potent endogenous agonists of PPARα. Furthermore, genetic ablation or pharmacological inhibition of PPARα abolished the protective effects of MG53. These findings reveal a crucial role of MG53-PPARα axis in driving the secretory lineage commitment of ISCs, especially during injury response, highlighting the important therapeutic potential of targeting MG53-PPARα signaling for IBD treatment and marking PPARα agonists as novel therapies for IBD caused by various etiologies.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"17 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260586","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":"Single-cell transcriptional dissection illuminates an evolution of immunosuppressive microenvironment during pancreatic ductal adenocarcinoma metastasis","authors":"Xiaowei Liu, Jinen Song, Meiling Yuan, Fengli Zuo, Huihui Li, Leyi Tang, Xinmin Wang, Xueyan Wang, Qian Xiao, Li Li, Xinyu Liu, Zhankun Yang, Jianlin Wu, Jing Jing, Xuelei Ma, Hubing Shi","doi":"10.1038/s41392-025-02265-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02265-0","url":null,"abstract":"<p>How the host immune system loses its surveillance function during the evolution from normal cell to malignancy is still largely unknown. Here, we investigate the dynamics changes of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment by profiling 132,115 single-cell transcriptomes derived from 51 tissues, including healthy pancreatic tissue, non-metastatic PDAC primary tumors, metastatic primary tumors, and patient-matched liver metastases. The cellular proportion, bio-functional, and interaction between each cell type are carefully characterized. Aberrant copy number variations (CNVs) indicating malignant intensity are identified at chromosomes 7 and 20 of epithelial cells during tumor development. A bio-functional transition of predominant genes from physiology to pancreatic oncogenesis and metastasis is observed. Combinatorial analysis of epithelial cells and immunocytes indicates a gradient loss of immune surveillance during the malignant transformation. By dissecting cellular interaction, we unravel an incremental tumor cell-triggered apoptosis of DCs through molecular pair ANXA1-FPR1/3. Consequently, the activation and infiltration of cytotoxic CD8⁺ T cells are dampened progressively. Remarkably, we unveil a novel subtype of stress-response NK cells (strNK), which are characterized by robust proliferation, diminished cytolytic capabilities, and negative immune regulation. Notably, the presence of strNK cells is associated with poor prognosis of PDAC patients, implying a potential pro-tumor function. Taken together, our results not only shed light on the intricate mechanisms underlying step-wise evasion of immune surveillance during PDAC tumor development, but also provide a potential strategy for holding back malignant transition by reinforcing DCs’ function.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"7 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237816","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":"Microbiota-derived butyrate alleviates asthma via inhibiting Tfh13-mediated IgE production","authors":"Baichao Yu, Chong Pei, Wenjun Peng, Yongkun Zheng, Ying Fu, Xueqi Wang, Wenjun Wang, Zhiqiang Wang, Yong Chen, Qi Wang, Kameina Zhuma, Yiyuan Gao, Yun Xing, Mengxia Jiao, Ronghua Liu, Feifei Luo, Dan Zhang, Jingbo Qie, Hui Yang, Meiling Jin, Luman Wang, Yiwei Chu","doi":"10.1038/s41392-025-02263-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02263-2","url":null,"abstract":"<p>Gut microbiota-derived short-chain fatty acids (SCFAs) impact asthma outcomes, highlighting the importance of understanding the disease mechanisms through the gut–lung axis. In this study, we identified that among SCFAs, butyrate uniquely alleviates asthma through specifically inhibiting a newly identified pathogenic T follicular helper (Tfh) cell subset, Tfh13 cells. Tfh13 cell depletion (<i>Il13</i>^<i>Cre/+</i><i>Bcl6</i>^<i>fl/fl</i>) or adoptive transfer of Tfh13 cells in an OVA-induced asthma model conclusively demonstrated their indispensable role in driving anaphylactic IgE production and asthma pathogenesis. Mechanistically, the inhibitory function of butyrate on Tfh13 cells is mediated by the interaction between butyrate and G-protein coupled receptor 43 (GPR43), leading to the suppression of p38 MAPK/NF-κB signaling in Tfh13 cells. To address the clinically observed deficiency of butyrate in patients with asthma and recapitulated in murine models, we developed a novel therapeutic strategy using a butyrate-yielding diet enriched with butylated high amylose maize starch (HAMSB). Remarkably, supplementation with HAMSB diet in murine and humanized asthma models significantly reduced Tfh13 cell frequencies and anaphylactic IgE levels, leading to significantly improved disease outcomes. Our findings not only unveil a novel mechanism underlying butyrate-mediated asthma alleviation, termed the butyrate–Tfh13–IgE axis, but also propose a clinically translatable dietary intervention strategy targeting microbial metabolites for stopping asthma.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"116 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144228740","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}